Transmucosal electrical stimulation

ABSTRACT

Apparatus is provided for modifying a property of a brain of a subject, including at least one electrode, configured to be positioned in a vicinity of a mucous membrane of a palate of an oral cavity of the subject. A control unit is configured to drive the electrode to apply an electrical current to the mucous membrane, and to configure the current to be capable of inducing an increase in cerebral blood flow (CBF) of the subject. Other embodiments are also described.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 11/349,020, filed Feb. 7, 2006, entitled: “SPG stimulation via thegreater palatine canal, which is a continuation-in-part of U.S. patentapplication Ser. No. 10/783,113, filed Feb. 20, 2004, entitled,“Stimulation for acute conditions,” which issued as U.S. Pat. No.7,117,033, and is assigned to the assignee of the present applicationand is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to medical procedures andelectrical devices. More specifically, the invention relates to the useof electrical devices for implantation in the head, for example, in thenasal cavity.

BACKGROUND OF THE INVENTION

PCT Publication WO 01/85094 to Shalev and Gross, which is assigned tothe assignee of the present patent application and is incorporatedherein by reference, describes apparatus for modifying a property of abrain of a patient, including electrodes applied to a sphenopalatineganglion (SPG) or a neural tract originating in or leading to the SPG. Acontrol unit drives the electrodes to apply a current capable ofinducing (a) an increase in permeability of a blood-brain barrier (BBB)of the patient, (b) a change in cerebral blood flow of the patient,and/or (c) an inhibition of parasympathetic activity of the SPG.

U.S. Pat. No. 6,853,858 to Shalev, which is assigned to the assignee ofthe present application and is incorporated herein by reference,describes apparatus for delivering a Non Steroidal Anti-InflammatoryDrug (NSAID) supplied to a body of a subject for delivery to at least aportion of a central nervous system (CNS) of the subject via a systemicblood circulation of the subject. The apparatus includes a stimulatoradapted to stimulate at least one site of the subject, so as to cause anincrease in passage of the NSAID from the systemic blood circulationacross a blood brain barrier (BBB) of the subject to the portion of theCNS, during at least a portion of the time that the NSAID is present inthe blood, the site selected from the list consisting of: asphenopalatine ganglion (SPG), an anterior ethmoidal nerve, a posteriorethmoidal nerve, a communicating branch between an anterior ethmoidalnerve and a retro-orbital branch of an SPG, a communicating branchbetween a posterior ethmoidal nerve and a retro-orbital branch of anSPG, a greater palatine nerve, a lesser palatine nerve, a sphenopalatinenerve, a communicating branch between a maxillary nerve and an SPG, anasopalatine nerve, a posterior nasal nerve, an infraorbital nerve, anotic ganglion, an afferent fiber going into the otic ganglion, anefferent fiber going out of the otic ganglion, a vidian nerve, a greatersuperficial petrosal nerve, and a lesser deep petrosal nerve.

US Patent Application Publication 2004/0220644 to Shalev et al., whichis assigned to the assignee of the present application and isincorporated herein by reference, describes a method for treating asubject, comprising positioning at least one electrode at least one siteof the subject for less than about 3 hours, applying an electricalcurrent to the site of the subject, and configuring the current toincrease cerebral blood flow (CBF) of the subject, so as to treat acondition of the subject. The site is selected from the list consistingof: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesserpalatine nerve, a sphenopalatine nerve, a communicating branch between amaxillary nerve and an SPG, an otic ganglion, an afferent fiber goinginto the otic ganglion, an efferent fiber going out of the oticganglion, an infraorbital nerve, a vidian nerve, a greater superficialpetrosal nerve, and a lesser deep petrosal nerve. Also described is anapparatus comprising an elongated support element having a length ofbetween about 1.8 cm and about 4 cm, and having a proximal end and adistal end; one or more electrodes fixed to the support element in avicinity of the distal end thereof; a receiver, fixed to the supportelement in a vicinity of the proximal end thereof; and a control unit,adapted to be coupled to the receiver, and adapted to drive theelectrodes to apply an electrical current to tissue of the subject, andconfigure the current to have a pulse frequency of between about 10 Hzand about 50 Hz, an amplitude of between about 0.2 V and about 10 V, apulse width of between about 50 microseconds and about 5 milliseconds,and, in alternation, on periods of between about 1 second and about 2minutes, and off periods of between about 1 second and about 2 minutes.

The following patent application publications, all of which are assignedto the assignee of the present application and are incorporated hereinby reference, may be of interest: WO 03/090599, WO 03/105658, WO04/010923, WO 04/043218, WO 04/044947, WO 04/045242, WO 04/043217, WO04/043334, WO 05/030025, and WO 05/030118.

U.S. Pat. No. 6,526,318 to Ansarinia and related PCT Publication WO01/97905 to Ansarinia, which are incorporated herein by reference,describe a method for the suppression or prevention of various medicalconditions, including pain, movement disorders, autonomic disorders, andneuropsychiatric disorders. The method includes positioning an electrodeon or proximate to at least one of the patient's SPG, sphenopalatinenerves, or vidian nerves, and activating the electrode to apply anelectrical signal to such nerve. In a further embodiment for treatingthe same conditions, the electrode used is activated to dispense amedication solution or analgesic to such nerve.

U.S. Pat. No. 6,405,079 to Ansarinia, which is incorporated herein byreference, describes a method for the suppression or prevention ofvarious medical conditions, including pain, movement disorders,autonomic disorders, and neuropsychiatric disorders. The method includespositioning an electrode adjacent to or around a sinus, the duraadjacent a sinus, or falx cerebri, and activating the electrode to applyan electrical signal to the site. In a further embodiment for treatingthe same conditions, the electrode dispenses a medication solution oranalgesic to the site.

U.S. Pat. No. 6,788,975 to Whitehurst et al., which is incorporatedherein by reference, describes an implantable stimulator with at leasttwo electrodes that is small enough to have the electrodes locatedadjacent to a nerve structure at least partially responsible forepileptic seizures. The nerve structure may include a trigeminalganglion or ganglia, a trigeminal nerve, or a branch of a trigeminalnerve, a greater occipital nerve, lesser occipital nerve, thirdoccipital nerve, facial nerve, glossopharyngeal nerve, or a branch ofany of these neural structures. Electrical stimulation of such targetsmay provide significant therapeutic benefit in the management ofepilepsy.

U.S. Pat. No. 5,716,377 to Rise et al., which is incorporated herein byreference, describes techniques for stimulating the brain to treatmovement disorders resulting in abnormal motor behavior by means of animplantable signal generator and electrode. A sensor is used to detectthe symptoms resulting from the motion disorder. A microprocessoralgorithm analyzes the output from the sensor in order to regulate thestimulation delivered to the brain.

U.S. Pat. No. 6,415,184 to Ishikawa et al., which is incorporated hereinby reference, describes a ball semiconductor for stimulating a mass ofnervous system brain tissue for therapeutic purposes. The ball isembedded in a mass of nervous system tissue of a brain. Electricalpulses generated and transmitted to the ball by a remote electricalpulse generator system are picked up by a receiving antenna of the ball,and are applied to an electrode pair of the ball to cause the mass ofnervous system tissue of the brain located between output pads of theelectrode to become stimulated, as therapy for a pathological condition,such as epilepsy.

U.S. Pat. No. 6,606,521 to Paspa et al., which is incorporated herein byreference, describes an implantable medical lead having markings, whichaid in the accurate localization of lead electrodes at a specific pointof the brain for neurostimulation. Also described is an implantablemedical lead having a removable extension that provides a minimal lengthof excess lead protruding from the lead insertion site. The lead andmethod of implantation facilitate use of a neurostimulator device thatis implanted directly in a patient's cranium.

U.S. Pat. No. 6,591,138 to Fischell et al., which is incorporated hereinby reference, describes a system for treating neurological conditions bylow-frequency time varying electrical stimulation. The system includesan electrical device for applying such low-frequency energy, in a rangebelow approximately 10 Hz, to the patient's brain tissue. An implantableembodiment applies direct electrical stimulation to electrodes implantedin or on the patient's brain, while a non-invasive embodiment causes amagnetic field to induce electrical currents in the patient's brain.

U.S. Pat. No. 6,343,226 to Sunde et al., which is incorporated herein byreference, describes a quadripolar deep brain stimulation electrode fortreating symptoms of central and peripheral nervous system disorders,such as Parkinson's disease, epilepsy, psychiatric illness, andintractable pain. It is important to determine the optimal placement ofan implanted electrode. An electrode device is described that allowsstimulation of a large volume of neural tissue in combination withsimultaneous microelectrode recording. The device is described asallowing for a less traumatic localization of the optimal neuralstimulation area by microelectrode recording in combination with theplacement of the permanent deep brain stimulation electrode.

US Patent Application Publication 2005/0065427 to Magill et al., whichis incorporated herein by reference, describes a method for locating theposition of a selected neural center in the central nervous system,including stimulating neurons at a first central nervous systemposition, measuring the field potential evoked at a second centralnervous system position, and comparing the evoked field potentialagainst a known evoked field potential from said neural center.

US Patent Application Publication 2005/0113877 to Spinelli et al., whichis incorporated herein by reference, describes implantable devices andmethods for treating various disorders of the pelvic floor by means ofelectrical stimulation of the pudendal or other nerves.Neurophysiological monitoring is utilized to assess the evoked responsesof the pudendal nerve, and thereby to provide a method for determiningthe optimal stimulation site.

U.S. Pat. No. 5,314,495 to Kovacs, which is incorporated herein byreference, describes a microelectrode interface for localizing thestimulation and recording of action potentials at a portion of a nervoussystem. A circuit is described for applying current only to one or moreselected pairs of microelectrodes in an array of microelectrodes. Rowand column select lines, switches and multiplexes are used for passingcurrent only between pairs of microelectrodes at selected locations inthe array for stimulating a portion of a nervous system only at selectedlocations.

The following patents and patent publications, all of which areincorporated herein by reference, may be of interest: U.S. Pat. No.5,756,071 to Mattern et al., U.S. Pat. No. 5,752,515 to Jolesz et al.,PCT Publications WO 03/084591, WO 03/020350, WO 03/000310, WO 02/068031,and WO 02/068029 to Djupesland, US Patent Application Publication2003/0079742 to Giroux, U.S. Pat. Nos. 5,725,471 and 6,086,525 to Daveyet al., PCT Publication WO 02/32504 to Zanger et al., US PatentApplication Publication 2003/0050527 to Fox et al., U.S. Pat. No.6,432,986 to Levin, PCT Publication WO 99/03473 to Levin, U.S. Pat. No.6,491,940 to Levin, US Patent Application 2003/0133877 to Levin, and PCTPublication WO 00/44432 to Levin, US Patent Application 2001/0004644 toLevin, PCT Publication WO 01/43733 to Levin, U.S. Pat. No. 4,867,164 toZabara, U.S. Pat. Nos. 6,341,236 and 6,671,556 to Osorio et al., U.S.Pat. No. 6,671,555 to Gielen et al., U.S. Pat. No. 5,978,702 to Ward etal., U.S. Pat. No. 6,205,359 to Boveja, U.S. Pat. No. 6,470,212 toWeijand et al., U.S. Pat. No. 6,640,137 to MacDonald, U.S. Pat. No.6,735,475 to Whitehurst et al., PCT Publication WO 01/97906 towhitehurst, U.S. Pat. No. 6,922,590 to Whitehurst, PCT Publication WO05/062829 to Whitehurst et al., and US Patent Application Publication2005/0154419 to Whitehurst et al.

The following references, which are incorporated herein by reference,may be useful:

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SUMMARY OF THE INVENTION

In an embodiment of the present invention, an oral appliance is providedthat is adapted to be brought into contact with a mucous membrane of apalate of an oral cavity of a subject. The appliance comprises one ormore electrodes, which are driven to apply transmucosal electricalstimulation to nerve fibers within or immediately above the mucousmembrane, which fibers directly innervate an SPG of the subject.Typically, but not necessarily, such stimulation is performed while thesubject is under general anesthesia or sedation. Such transmucosalstimulation may require less current than the transcutaneous stimulationdescribed hereinabove.

In some embodiments of the present invention, a neural stimulationsystem comprises an implantable neural stimulator, an oral element, andan external control unit. The neural stimulator comprises an elongatedsupport element, one or more electrodes fixed to the support element ina vicinity of a distal end thereof, and a wireless coupling elementphysically attached to the support element, e.g., in a vicinity of aproximal end thereof. The stimulator is adapted to be passed through agreater palatine foramen of a palate of an oral cavity of a subject intoa greater palatine canal, such that the electrodes are brought into avicinity of a sphenopalatine ganglion (SPG). For some applications, thestimulator comprises a locking element, which is adapted to hold thestimulator in place after implantation.

In some embodiments of the present invention, the distal end of thesupport element comprises a surgical punch, which enables the stimulatorto be passed through the palate in a minimally-invasive procedure,without requiring a prior surgical incision in the mucosa. The wirelesscoupling element is sufficiently small so as to be able to pass throughthe punch incision without requiring the incision to be surgicallyenlarged. The use of the punch to insert the stimulator, rather than amore complicated surgical procedure, generally allows the stimulator tobe quickly implanted in the subject.

The oral element of the system is adapted to be placed in the oralcavity, e.g., in a vicinity of or in contact with the roof of the oralcavity or the alveolar process of the maxilla, in a vicinity of theimplanted wireless coupling element of the stimulator. The oral elementcomprises a power source, such as a rechargeable or disposable battery,and at least one wireless coupling element. The wireless couplingelement of the oral element is adapted to wirelessly transmit energy tothe wireless coupling element of the stimulator, for powering thestimulator. For some applications, the wireless coupling element of theoral element is additionally configured to transmit and/or receive datato/from the wireless coupling element of the stimulator. For someapplications, the oral element transmits/receives data to/from theexternal control unit. Alternatively, the stimulator transmits/receivesdata directly to/from the external control unit.

In some embodiments of the present invention, a neural stimulationsystem comprises an implantable neural stimulator and an externalcontrol unit. The neural stimulator comprises an elongated supportelement, one or more electrodes fixed to the support element in avicinity of a distal end thereof, and an implantable antenna coupled tothe support element in a vicinity of a proximal end thereof. The supportelement is adapted to be passed through a palate of an oral cavity of asubject into a greater palatine canal, such that the electrodes arebrought into a vicinity of a SPG. For some applications, the implantableantenna comprises a submucosal antenna comprising a thin, flexible sheetcomprising at least one coil. The submucosal antenna is adapted to beimplanted in the roof of the oral cavity between the oral mucosa and thepalate, e.g., the hard palate, and to conform to the shape of thepalate. For other applications, the implantable antenna comprises a coilantenna, which is coiled around at least a portion of the supportelement. In these embodiments, the system typically lacks an oralelement. Instead, the external control unit is adapted to transmit powerdirectly (typically as radiofrequency (RF) energy) to the submucosalantenna of the stimulator, and to transmit and/or receive data directlyto/from the submucosal antenna. Typically, the external control unit isadapted to be placed in a vicinity of a head of the subject, such as ina vicinity of an ear of the subject, e.g., coupled to the ear.

In some embodiments of the present invention, the one or more electrodesof the stimulator comprise an array of electrodes, at least a portion ofwhich are adapted to be separately activatable. After the stimulator hasbeen implanted, the stimulation system uses a calibration algorithm toactivate, during a plurality of calibration periods, respectivedifferent sets of one or more of the electrodes, in order to determinewhich set's activation causes a level of stimulation of the SPG closestto a desired level. Use of such an algorithm generally obviates the needto adjust the location of the stimulator after it has been implanted.For some applications, the level of stimulation of the SPG is determinedby receiving feedback directly from the SPG, or from other neural tissuein a vicinity of the SPG, i.e., by using at least a portion of theelectrodes to directly measure a level of stimulation of the SPG or theother neural tissue at or in a vicinity of the site(s) of thestimulation by the electrodes. Alternatively, the level of stimulationof the SPG is determined by assessing an indirect physiologicalparameter of the subject related to the level of SPG stimulation, suchas cerebral blood flow (CBF).

In some embodiments of the present invention, the elongated supportelement of the stimulator has a length of between about 1.8 and about 4cm, such as between about 1.8 cm and about 3 cm, e.g., between about 2.6and about 3 cm, such as about 2.8 cm, and/or has a curvature thatfollows that of the greater palatine canal.

For some applications, treatment with the systems described herein isapplied as soon as possible after diagnosis of the condition, such as inan emergency room or wherever the subject happens to be. For otherapplications, the system is appropriate for longer-term treatment, suchas for modulating the permeability of the BBB, modulating cerebral bloodflow (CBF), rehabilitation after brain events, or prevention and/ortreatment of epilepsy. For some applications, the stimulator is adaptedto be implanted for at least one week, e.g., at least one month, whilefor other applications, the stimulator is adapted to be implanted forless than one week, e.g., less than one day.

In some embodiments of the present invention, an electrical stimulatordrives current into at least one “modulation target site” (MTS), asdefined hereinbelow. Typically, the stimulator drives the current inorder to control and/or modify SPG-related behavior, e.g., in order toinduce changes in cerebral blood flow and/or to modulate permeability ofthe blood-brain barrier (BBB). Concurrently with or after placement ofthe stimulator near or in contact with an MTS, at least onephysiological indicator of cerebral blood flow (CBF) is observed ormeasured. Optimization of placement of the stimulator onto theappropriate neural structure is performed by activating the stimulator,and generally simultaneously monitoring CBF while manipulating theplacement of the stimulator so as to increase or decrease CBF, asappropriate. Alternatively or additionally, a similar optimizationprocess is performed, either during or after implantation of thestimulator, to determine parameters of the applied current that achievea desired effect, as indicated by CBF.

In the present patent application, a “modulation target site” (MTS)consists of:

-   -   an SPG (also called a pterygopalatine ganglion);    -   a nerve of the pterygoid canal (also called a vidian nerve),        such as a greater superficial petrosal nerve (a preganglionic        parasympathetic nerve) or a lesser deep petrosal nerve (a        postganglionic sympathetic nerve);    -   a greater palatine nerve;    -   a lesser palatine nerve;    -   a sphenopalatine nerve;    -   a communicating branch between the maxillary nerve and the        sphenopalatine ganglion;    -   an otic ganglion;    -   an afferent fiber going into the otic ganglion;    -   an efferent fiber going out of the otic ganglion; or    -   an infraorbital nerve.

It is to be appreciated that while some embodiments of the invention aregenerally described herein with respect to electrical transmission ofpower and electrical modulation of tissue, other modes of energytransport may be used as well. Such energy includes, but is not limitedto, direct or induced electromagnetic energy, radiofrequency (RF)transmission, mechanical vibration, ultrasonic transmission, opticalpower, and low power laser energy (via, for example, a fiber opticcable).

It is further to be appreciated that whereas some embodiments of thepresent invention are described with respect to application ofelectrical currents to tissue, this is to be understood in the contextof the present patent application and in the claims as beingsubstantially equivalent to applying an electrical field, e.g., bycreating a voltage drop between two electrodes.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for modifying a property of a brain of asubject, including:

at least one electrode, adapted to be positioned in a vicinity of amucous membrane of a palate of an oral cavity of the subject; and

a control unit, adapted to drive the electrode to apply an electricalcurrent to the mucous membrane, and to configure the current to becapable of inducing an increase in permeability of a blood-brain barrier(BBB) of the subject.

For some applications, the control unit is adapted to configure thecurrent to have a magnitude sufficient to activate a sphenopalatineganglion (SPG) of the subject via nerve fibers in physical contact withthe mucous membrane.

For some applications, the control unit is adapted to configure thecurrent to increase the permeability of the BBB to a magnitudesufficient to treat a condition of the subject. Alternatively oradditionally, the control unit is adapted to configure the current toincrease the permeability of the BBB to a magnitude sufficient toperform a diagnosis of a condition of the subject.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for modifying a property of a brain of asubject, including:

at least one electrode, adapted to be positioned in a vicinity of amucous membrane of a palate of an oral cavity of the subject; and

a control unit, adapted to drive the electrode to apply an electricalcurrent to the mucous membrane, and to configure the current to becapable of inducing an increase in cerebral blood flow (CBF) of thesubject.

For some applications, the control unit is adapted to configure thecurrent to have a magnitude sufficient to activate a sphenopalatineganglion (SPG) of the subject via nerve fibers in physical contact withthe mucous membrane.

For some applications, the control unit is adapted to configure thecurrent to increase the CBF to a magnitude sufficient to treat acondition of the subject.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for modifying a property of a brain of asubject, including applying an electrical current to a mucous membraneof a palate of an oral cavity of the subject, the current capable ofinducing an increase in permeability of a blood-brain barrier (BBB) ofthe subject.

In an embodiment, the method includes administering a sedative to thesubject in conjunction with applying the current. Alternatively oradditionally, the method includes administering an anesthetic to thesubject in conjunction with applying the current.

In an embodiment, the method includes performing a diagnostic activitywith respect to a condition of the subject, in conjunction with theincrease in permeability of the BBB.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for modifying a property of a brain of asubject, including applying an electrical current to a mucous membraneof a palate of an oral cavity of the subject, the current capable ofinducing an increase in cerebral blood flow (CBF) of the subject.

There is therefore provided, in accordance with an embodiment of thepresent invention, apparatus for application to a subject, including:

an elongated support element having a length of between 1.8 cm and 4 cm,and having proximal and distal ends;

one or more electrodes fixed to the support element in a vicinity of thedistal end thereof, and adapted to apply an electrical current to asphenopalatine ganglion (SPG) of the subject;

a receiver, fixed to the support element, and electrically coupled tothe electrodes; and

a wireless transmitter, adapted to be placed in an oral cavity of thesubject, and to be wirelessly coupled to the receiver.

For some applications, the wireless transmitter is adapted to beelectromagnetically coupled to the receiver, or wirelessly coupled tothe receiver via ultrasound. Alternatively, the receiver is adapted tobe wireless coupled to the wireless transmitter by induction. For someapplications, the electrodes are adapted to apply the current using onlypower received by the receiver from the wireless transmitter.

For some applications, the apparatus includes an oral appliance, adaptedto be fixed to the transmitter, and shaped so as to define a surfacethat fits closely to a roof of the oral cavity. Alternatively, theapparatus includes an oral appliance, adapted to be fixed to thetransmitter, and adapted to be coupled to a tooth of the subject, and/oradapted to be coupled to gingival covering an alveolar process of thesubject.

For some applications, the apparatus includes an oral appliance, whichincludes: a capsule, which is configured to be placed and held betweenan alveolar process and an inner surface of a cheek of the subject; thetransmitter; and an elongated coupling element, which couples thetransmitter to the capsule. For some applications, the transmitter isadapted to be implanted in a tooth of the subject. For someapplications, at least a portion of the receiver is adapted to bepositioned between mucosa and a hard palate of the subject.Alternatively, at least a portion of the receiver is adapted to bepositioned between mucosa and an alveolar process of a maxilla of thesubject.

For some applications, the apparatus includes one or more electrodeleads, which electrically couple the receiver to the electrodes, andwhich serve as the support element. For some applications, the distalend of the support element includes a surgical punch.

In an embodiment, the apparatus includes an external control unit,adapted to be placed outside of a head of the subject, which includes acontrol unit wireless coupling element, which is adapted to wirelesslytransmit data from the control unit to the receiver.

For some applications, the electrodes include exactly one cathode andexactly one anode, and a closest distance between the cathode and theanode is greater than a closest distance between any portion of thecathode and any portion of the SPG when the electrodes are positioned ina vicinity of the SPG.

For some applications, the support element, electrodes, and receiver areadapted to be implanted in the subject for at least one week.Alternatively, the support element, electrodes, and receiver are adaptedto be implanted in the subject for less than one day.

For some applications, the support element is sufficiently rigid toenable insertion of the support element into a body of the subject bypushing from a vicinity of the proximal end of the support element.

For some applications, the support element has a curvature that followsthat of a greater palatine canal of the subject.

In an embodiment, the receiver is fixed to the support element in avicinity of the proximal end of the support element. For someapplications, the apparatus includes a circuit module, which is fixed tothe proximal end of the support element, and which includes a printedcircuit board and the receiver. For some applications, the circuitmodule includes one or more layers of coating applied thereto.

For some applications, the support element is folded in a vicinity ofthe proximal end of the support element, at an angle approximately equalto an angle between a greater palatine canal of the subject and a hardpalate of the subject in a vicinity of a greater palatine foramen of asubject, and the circuit module is adapted to be placed submucosallyagainst a lower surface of the hard palate.

Alternatively, the proximal end of the support element is fixed to thecircuit module such that an angle between the support element and asurface of the circuit module is approximately equal to an angle betweena greater palatine canal of the subject and a hard palate of the subjectin a vicinity of a greater palatine foramen of a subject, and thecircuit module is adapted to be placed submucosally against a lowersurface of the hard palate. For some applications, the proximal end ofthe support element is fixed to the circuit module in a vicinity of acenter of the surface of the circuit module, or in a vicinity of an edgeof the surface of the circuit module.

For some applications, the proximal end of the support element is fixedto the circuit module in a vicinity of an edge of the circuit module,and the circuit module is adapted to be placed submucosally against analveolar process of a maxilla of the subject.

In an embodiment, the apparatus includes: an external control unit,adapted to be placed outside of a head of the subject, the externalcontrol unit including a control unit wireless coupling element; asupport element wireless coupling element, coupled to the supportelement; and circuitry, coupled to the support element, and adapted todrive the wireless coupling element to wirelessly transmit feedbackinformation to the external control unit. For some applications, thesupport element wireless coupling element and the receiver include acommon transducer element.

In an embodiment, the apparatus includes: an oral element, whichincludes the wireless transmitter; an external driver, which includes apower source and circuitry, and which is adapted to be placed outside abody of the subject; and one or more wires which electrically couple theexternal driver to the oral element. For some applications, the externaldriver is adapted to be physically coupled to the body of the subject.For some applications, the apparatus includes an external control unit,which is adapted to be placed outside the body of the subject, and whichis coupled to the external driver.

In an embodiment, the apparatus includes an oral element, which includesthe wireless transmitter and oral element circuitry coupled to thewireless transmitter; and a power source, adapted to provide power tothe wireless transmitter and circuitry. For some applications, the oralelement includes the power source. Alternatively, the power source isadapted to be placed outside a body of the subject, and to be coupled tothe oral element. For some applications, the apparatus includes receivercircuitry, which is coupled to the support element and the receiver, andthe oral element circuitry is adapted to drive the wireless transmitterto transmit energy that does not include a stimulation waveform forapplication by the electrodes, the receiver is adapted to receive theenergy, and the receiver circuitry is adapted to generate thestimulation waveform using the energy, and to drive the electrodes toapply the stimulation waveform to the SPG.

For some applications, the apparatus includes receiver circuitry, whichis coupled to the support element and the receiver, and the oral elementcircuitry is adapted to drive the wireless transmitter to transmitenergy that includes a stimulation waveform for application by theelectrodes, the receiver is adapted to receive the energy, and thereceiver circuitry is adapted to drive the electrodes to apply thestimulation waveform to the SPG.

For some applications, the oral element is adapted to be fixed to a roofof the oral cavity. Alternatively, the oral element is adapted totemporarily placed against the roof of the oral cavity, without beingfixed thereto.

For some applications, the apparatus includes an external control unit,adapted to be placed outside of a head of the subject, the externalcontrol unit including a control unit wireless coupling element, whichis adapted to wirelessly transmit data from the control unit to the oralelement, and the oral element is adapted to wirelessly transmit thereceived data to the receiver. For some applications, the oral elementis adapted to wirelessly transmit feedback information to the externalcontrol unit.

In an embodiment, the support element has a length of between 1.8 and 3cm, such as between 2.6 and 3 cm.

In an embodiment, at least a portion of the support element is adaptedto be placed in a greater palatine canal of the subject. For someapplications, the support element includes a lock, adapted to hold thesupport element in place after insertion thereof into the greaterpalatine canal. For some applications, the support element is adapted tobe inserted into the greater palatine canal such that no portion of thesupport element protrudes into the oral cavity. For example, thereceiver may be adapted to be contained entirely within the greaterpalatine canal when the support element is inserted into the greaterpalatine canal. For some applications, the receiver includes at leastone coil that is coiled around at least a portion of the supportelement. For some applications, the at least one coil includes aplurality of coils which are oriented in a plurality of respectiveorientations.

For some applications, the apparatus includes circuitry adapted tomeasure, using at least one of the electrodes, a level of stimulationinduced by the applied current, such as a level of stimulation of theSPG.

For some applications, the one or more electrodes include a plurality ofelectrodes, and the apparatus includes circuitry adapted to perform acalibration procedure by activating, during a plurality of calibrationperiods, respective different sets of one or more of the electrodes. Forsome applications, the circuitry is adapted to measure, during each ofthe calibration periods, using at least one of the electrodes, anindication of a level of stimulation induced by the activation of therespective set of electrodes, such as a level of stimulation of the SPG.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for application to a subject, including:

one or more electrodes adapted to apply an electrical current to tissueof the subject selected from the group consisting of: a sphenopalatineganglion (SPG), a greater palatine nerve, a lesser palatine nerve, asphenopalatine nerve, a communicating branch between a maxillary nerveand an SPG, an otic ganglion, an afferent fiber going into the oticganglion, an efferent fiber going out of the otic ganglion, aninfraorbital nerve, a vidian nerve, a greater superficial petrosalnerve, and a lesser deep petrosal nerve;

a receiver, electrically coupled to the one or more electrodes; and

a wireless transmitter, adapted to be placed in an oral cavity of thesubject, and to be wirelessly coupled to the receiver.

In an embodiment, the tissue includes the SPG, and the one or moreelectrodes are adapted to apply the current to the SPG.

For some applications, the wireless transmitter is adapted to beelectromagnetically coupled to the receiver, or wirelessly coupled tothe receiver via ultrasound. Alternatively, the receiver is adapted tobe wirelessly coupled to the wireless transmitter by induction.

For some applications, the apparatus includes an oral appliance, adaptedto be fixed to the transmitter, and shaped so as to define a surfacethat fits closely to a roof of the oral cavity.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for application to a subject, including:

an elongated support element adapted to be placed within a greaterpalatine canal of the subject, sized to extend from a palate of thesubject to a sphenopalatine ganglion (SPG) of the subject, and havingdistal and proximal ends; and

one or more electrodes fixed to the support element in a vicinity of thedistal end thereof; and

a control unit, coupled to the electrodes, and adapted to drive theelectrodes to apply an electrical current to the SPG.

In an embodiment, the support element is adapted to have a length thatis adjustable during an implantation procedure. For some applications,the support element includes at least two portions that aretelescopically coupled to one another. For some applications, theapparatus includes a sleeve, which surrounds a portion of the supportelement. For some applications, a portion of the support element isshaped so as to define one or more accordion pleats. For someapplications, the apparatus includes one or more electrode leads coupledto the electrodes, which leads serve as the support element and areaccordion-pleated, a portion of which leads are helically wound so as toform a spring, or which leads are shaped so as to define at least oneomega-shaped portion.

In an embodiment, the support element includes a support elementelectrical contact in a vicinity of the proximal end thereof, thecontrol unit includes a control unit electrical contact, and the controlunit is adapted to be placed in an oral cavity of the subject such thatthe control unit electrical contact is brought into physical contactwith the support element electrical contact, thereby coupling thecontrol unit to the electrodes. For some applications, the control unitis adapted to temporarily placed against a roof of the oral cavity,without being fixed thereto. For some applications, the control unit isadapted to be fixed to a roof of the oral cavity. For some applications,the support element electrical contact is adapted to be in sealedcontact with mucosa of the subject. Alternatively or additionally, thesupport element electrical contact includes a matrix, which is adaptedto promote mucosal tissue growth therein.

In an embodiment, the apparatus includes a receiver, which is fixed tothe support element; and a wireless transmitter, which is coupled to thecontrol unit, and which is adapted to be wirelessly coupled to thereceiver, thereby coupling the control unit to the electrodes. For someapplications, the wireless transmitter is adapted to be placed in anoral cavity of the subject. Alternatively, the wireless transmitter isadapted to be placed outside of a head of the subject. For someapplications, the apparatus includes an autonomically-powered powersupply physically coupled to the support element, which is adapted toprovide power for the electrodes, and the control unit is adapted towirelessly transmit data to the receiver.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus including an implantable neural stimulator,which includes:

one or more electrodes adapted to be placed in a vicinity of a greaterpalatine foramen of a subject; and

a control unit, coupled to the electrodes, and adapted to drive theelectrodes to apply an electrical current to a greater palatine nerve ofthe subject.

For some applications, the electrodes are adapted to be placed within 5mm of the greater palatine foramen. For some applications, theelectrodes are adapted to be contained entirely within a greaterpalatine canal of the subject. For some applications, at least a portionof the electrodes is adapted to be located between mucosa and a palateof the subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus including an implantable neuralstimulator, which includes:

one or more electrodes adapted to apply an electrical current to tissueof a subject selected from the group consisting of: a sphenopalatineganglion (SPG), a greater palatine nerve, a lesser palatine nerve, asphenopalatine nerve, a communicating branch between a maxillary nerveand an SPG, an otic ganglion, an afferent fiber going into the oticganglion, an efferent fiber going out of the otic ganglion, aninfraorbital nerve, a vidian nerve, a greater superficial petrosalnerve, and a lesser deep petrosal nerve;

an implantable submucosal antenna, which includes at least one coil, andis adapted to be implanted between oral mucosa and a palate of thesubject; and

one or more electrode leads, which electrically couple the submucosalantenna to the electrodes.

In an embodiment, the tissue includes the SPG, and the one or moreelectrodes are adapted to apply the current to the SPG.

In an embodiment, the submucosal antenna includes a flexible sheet,which includes the at least one coil.

For some applications, the apparatus includes an external driver, whichincludes a power source and circuitry, which is adapted to be placedoutside a body of the subject, and which is adapted to be wirelesslycoupled to the submucosal antenna; and an external control unit, whichis adapted to be placed outside the body of the subject, and which iscoupled to the external driver.

In an embodiment, the stimulator includes an elongated support elementhaving proximal and distal ends, which is adapted to be inserted into agreater palatine canal of the subject, and the one or more electrodesare coupled to the support element in a vicinity of the distal end, andthe submucosal antenna is coupled to the support element in a vicinityof the proximal end. For some applications, the support element has alength of between 2.6 cm and 3 cm. For some applications, the supportelement is adapted to have a length that is adjustable during animplantation procedure.

In an embodiment, the apparatus includes a control unit, adapted to bewirelessly coupled to the submucosal antenna. For some applications, thecontrol unit is adapted to transmit power and data to the submucosalantenna, and the stimulator is adapted to use the power to generate astimulation waveform at least in part responsively to the received data,and to drive the one or more electrodes to apply the stimulationwaveform. For some applications, the control unit is adapted to beplaced externally to a body of the subject, such as in a vicinity of ahead of the subject, e.g., in a vicinity of an ear of the subject.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus including an implantable neuralstimulator, which includes:

a plurality of electrodes adapted to apply an electrical current to asite of a subject selected from the group consisting of: asphenopalatine ganglion (SPG), a greater palatine nerve, a lesserpalatine nerve, a sphenopalatine nerve, a communicating branch between amaxillary nerve and an SPG, an otic ganglion, an afferent fiber goinginto the otic ganglion, an efferent fiber going out of the oticganglion, an infraorbital nerve, a vidian nerve, a greater superficialpetrosal nerve, and a lesser deep petrosal nerve; and

a control unit, coupled to the electrodes, and adapted to perform acalibration procedure by activating, during a plurality of calibrationperiods, respective different sets of one or more of the electrodes.

For some applications, the control unit is adapted to be placedexternally to a body of the subject, and to be wirelessly coupled to theelectrodes.

In an embodiment, the control unit is adapted to receive, during each ofthe calibration periods, an indication of a level of stimulation inducedby the activation of the respective set of electrodes, such as a levelof stimulation of the site. For some applications, the control unit isadapted to select the set of electrodes the activation of which inducedthe level of stimulation nearest a desired level of stimulation.

For some applications, the control unit is adapted to receive theindication of the level of stimulation, e.g., of the site, by using atleast a portion of the electrodes to measure the level of stimulation.For some applications, the control unit is adapted to measure, using theat least a portion of the electrodes, an electric field of nervoustissue, e.g., of the site, induced by the activation of the respectiveset of electrodes. For some applications, the at least a portion of theelectrodes includes one or more of the electrodes of the respective setof electrodes. For some applications, the at least a portion of theelectrodes includes one or more of the electrodes positioned in avicinity of the electrodes of the respective set of electrodes.

For some applications, the indication includes an indirect physiologicalparameter of the subject related to the level of the stimulation, andthe control unit is adapted to receive the indirect physiologicalparameter during each of the calibration periods. For some applications,the indirect physiological parameter includes an indication of cerebralblood flow (CBF) of the subject, and the control unit is adapted toreceive the indication of CBF. For some applications, the indirectphysiological parameter includes an indication of blood-brain barrier(BBB) permeability of the subject, and the control unit is adapted toreceive the indication of BBB permeability. For some applications, theapparatus includes a device adapted to measure the indirectphysiological parameter, and the control unit is adapted to receive theindirect physiological parameter measured by the device.

In an embodiment, the site includes the SPG, and the electrodes areadapted to apply the current to the SPG. For some applications, thestimulator includes an elongated support element having a distal end,and adapted to be inserted into a greater palatine canal of the subjectvia a palate of the subject, and the electrodes are coupled to thesupport element in a vicinity of the distal end.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus including an implantable neural stimulator,which includes:

a set of one or more electrodes adapted to be placed in a vicinity of asite of a subject selected from the group consisting of: asphenopalatine ganglion (SPG), a greater palatine nerve, a lesserpalatine nerve, a sphenopalatine nerve, a communicating branch between amaxillary nerve and an SPG, an otic ganglion, an afferent fiber goinginto the otic ganglion, an efferent fiber going out of the oticganglion, an infraorbital nerve, a vidian nerve, a greater superficialpetrosal nerve, and a lesser deep petrosal nerve; and

a control unit, coupled to the set of electrodes, and adapted to:

drive at least one of the electrodes to apply an electrical current tothe site, and

using at least one of the electrodes, measure a level of stimulationinduced by the applied current.

In an embodiment, the level of stimulation includes a level ofstimulation of the site induced by the applied current, and the controlunit is adapted to measure the level of stimulation of the site, usingthe at least one of the electrodes.

In an embodiment, the site includes the SPG, and the electrodes areadapted to be placed in the vicinity of the SPG.

For some applications, the control unit is adapted to measure the levelof stimulation using at least one of the at least one of the electrodesthat applies the current to the site. For some applications, the controlunit is adapted to measure the level of stimulation using at least oneof the electrodes positioned in a vicinity of the at least one of theelectrodes that applies the current to the site. For some applications,the control unit is adapted to measure, using the at least one of theelectrodes, an electric field of nervous tissue, e.g., of the site,induced by the applied current.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus including an implantable neural stimulator, whichincludes:

an elongated support element having a length of between 2.6 cm and 3 cm,having a distal end, and including, at the distal end, a surgical punchadapted to facilitate insertion of the support element through mucosa ofthe subject into a greater palatine canal of a subject, via a greaterpalatine foramen of the subject; and

one or more electrodes fixed to the support element in a vicinity of thedistal end thereof, and adapted to apply an electrical current to asphenopalatine ganglion (SPG) of the subject.

For some applications, the support element includes a lock, adapted tohold the support element in place after insertion thereof into thegreater palatine canal.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus including an implantable neural stimulator,which includes:

an elongated support element having a length of between 2.6 cm and 3 cm,having a distal end, and adapted to be placed in a greater palatinecanal of a subject;

one or more electrodes fixed to the support element in a vicinity of thedistal end thereof, and adapted to apply an electrical current to asphenopalatine ganglion (SPG) of the subject; and

a needle shaped so as to define a sharp distal end and a bore, whichbore is adapted to hold the support element and the electrodes duringinsertion of the support element and the electrodes into the greaterpalatine canal, and to be withdrawn from the greater palatine canalthereafter, leaving the support element and electrodes in the greaterpalatine canal.

For some applications, the support element includes a lock, adapted tohold the support element in place after insertion thereof into thegreater palatine canal.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus including an implantable neural stimulator,which includes:

one or more electrodes adapted to apply an electrical current to tissueof a subject selected from the group consisting of: a sphenopalatineganglion (SPG), a greater palatine nerve, a lesser palatine nerve, asphenopalatine nerve, a communicating branch between a maxillary nerveand an SPG, an otic ganglion, an afferent fiber going into the oticganglion, an efferent fiber going out of the otic ganglion, aninfraorbital nerve, a vidian nerve, a greater superficial petrosalnerve, and a lesser deep petrosal nerve;

a receiver, electrically coupled to the one or more electrodes;

an oral appliance, which includes:

-   -   a capsule, which is configured to be placed and held between an        alveolar process and an inner surface of a cheek of the subject;    -   a wireless transmitter, adapted to be wirelessly coupled to the        receiver; and    -   an elongated coupling element, which couples the transmitter to        the capsule; and

a power source, electrically coupled to the wireless transmitter.

In an embodiment, the capsule includes the power source. Alternatively,the apparatus includes a cable, and the power source is adapted to beplaced outside of a body of the subject, and is physically andelectrically coupled to the capsule via the cable.

For some applications, the capsule is generally cylindrical. For someapplications, the capsule includes a soft coating.

In an embodiment, the coupling element is configured such that thetransmitter is positioned on a lingual side of teeth of the subject whenthe capsule is held between the alveolar process and the inner surfaceof the cheek. For some applications, the coupling element is configuredto pass over an occlusal surface of one or more teeth of the subject.Alternatively, the coupling element is configured to pass around adistal surface of a most distal molar of the subject.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method including:

inserting an elongated support element into a body of a subject, theelement having a length of between about 1.8 cm and about 4 cm, andhaving proximal and distal ends;

wirelessly transmitting energy from within an oral cavity of thesubject;

receiving the energy at the support element; and

using the received energy, applying, from a vicinity of the distal endof the support element, an electrical current to a sphenopalatineganglion (SPG) of the subject.

In an embodiment, inserting the support element includes:

preparing a submucosal surface on a hard palate of the subject;

inserting the support element into a greater palatine canal of thesubject; and

placing a circuit module, which is fixed to the proximal end of thesupport element, against the prepared submucosal surface, and

receiving the energy at the support element includes receiving theenergy at the circuit module.

In an embodiment, inserting the support element includes:

preparing a submucosal surface on an alveolar process of a maxilla ofthe subject;

inserting the support element into a greater palatine canal of thesubject; and

placing a circuit module, which is fixed to the proximal end of thesupport element, against the prepared submucosal surface, and

receiving the energy at the support element includes receiving theenergy at the circuit module.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

wirelessly transmitting energy from within an oral cavity of a subject;

receiving the energy; and

using the received energy, applying an electrical current to tissue ofthe subject selected from the group consisting of: a sphenopalatineganglion (SPG), a greater palatine nerve, a lesser palatine nerve, asphenopalatine nerve, a communicating branch between a maxillary nerveand an SPG, an otic ganglion, an afferent fiber going into the oticganglion, an efferent fiber going out of the otic ganglion, aninfraorbital nerve, a vidian nerve, a greater superficial petrosalnerve, and a lesser deep petrosal nerve.

There is also provided, in accordance with an embodiment of the presentinvention, a method including:

inserting an elongated support element into a greater palatine canal ofthe subject, such that the support element extends from a palate of thesubject to a sphenopalatine ganglion (SPG) of the subject, the supportelement having a distal end; and

applying, from a vicinity of the distal end, an electrical current tothe SPG.

There is further provided, in accordance with an embodiment of thepresent invention, a method including applying an electrical current toa greater palatine nerve of a subject from a site in a vicinity of agreater palatine foramen of a subject.

There is still further provided, in accordance with an embodiment of thepresent invention, a method including:

implanting, between oral mucosa and a palate of the subject, asubmucosal antenna that includes at least one coil;

wirelessly transmitting energy to the submucosal antenna;

receiving the energy at the submucosal antenna; and

using the energy, applying an electrical current to tissue of a subjectselected from the group consisting of: a sphenopalatine ganglion (SPG),a greater palatine nerve, a lesser palatine nerve, a sphenopalatinenerve, a communicating branch between a maxillary nerve and an SPG, anotic ganglion, an afferent fiber going into the otic ganglion, anefferent fiber going out of the otic ganglion, an infraorbital nerve, avidian nerve, a greater superficial petrosal nerve, and a lesser deeppetrosal nerve.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method including performing a calibration procedureby applying an electrical current to an anatomical site of a subject,during a plurality of calibration periods, from respective differentsets of one or more stimulation sites in a vicinity of the anatomicalsite, the anatomical site selected from the group consisting of: asphenopalatine ganglion (SPG), a greater palatine nerve, a lesserpalatine nerve, a sphenopalatine nerve, a communicating branch between amaxillary nerve and an SPG, an otic ganglion, an afferent fiber goinginto the otic ganglion, an efferent fiber going out of the oticganglion, an infraorbital nerve, a vidian nerve, a greater superficialpetrosal nerve, and a lesser deep petrosal nerve.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

placing a set of one or more electrodes in a vicinity of a site of asubject selected from the group consisting of: a sphenopalatine ganglion(SPG), a greater palatine nerve, a lesser palatine nerve, asphenopalatine nerve, a communicating branch between a maxillary nerveand an SPG, an otic ganglion, an afferent fiber going into the oticganglion, an efferent fiber going out of the otic ganglion, aninfraorbital nerve, a vidian nerve, a greater superficial petrosalnerve, and a lesser deep petrosal nerve;

driving at least one of the electrodes to apply an electrical current tothe site; and

using at least one of the electrodes, measuring a level of stimulationinduced by the applied current.

There is also provided, in accordance with an embodiment of the presentinvention, a method including:

inserting, into a greater palatine canal of a subject, via a greaterpalatine foramen of the subject, an elongated support element having alength of between 2.6 cm and 3 cm and having a distal end, by using thedistal end of the support element to punch an incision in mucosa of thesubject; and

applying, from a vicinity of the distal end of the support element, anelectrical current to a sphenopalatine ganglion (SPG) of the subject.

There is further provided, in accordance with an embodiment of thepresent invention, a method including:

placing an elongated support element, having a length of between 2.6 cmand 3 cm and having a distal end, into a bore of a needle shaped so asto define a sharp distal end;

inserting, into a greater palatine canal of a subject, the needleholding the support element;

withdrawing the needle from the greater palatine canal thereafter,leaving the support element in the greater palatine canal; and

applying, from a vicinity of the distal end of the support element, anelectrical current to a sphenopalatine ganglion (SPG) of the subject.

There is still further provided, in accordance with an embodiment of thepresent invention, a method including:

placing a capsule between an alveolar process and an inner surface of acheek of a subject;

placing, in an oral cavity of the subject, a wireless transmittercoupled to the capsule by an elongated coupling element;

wirelessly transmitting energy from the wireless transmitter; andreceiving the energy, and, using the received energy, applying anelectrical current to tissue of the subject selected from the groupconsisting of: a sphenopalatine ganglion (SPG), a greater palatinenerve, a lesser palatine nerve, a sphenopalatine nerve, a communicatingbranch between a maxillary nerve and an SPG, an otic ganglion, anafferent fiber going into the otic ganglion, an efferent fiber going outof the otic ganglion, an infraorbital nerve, a vidian nerve, a greatersuperficial petrosal nerve, and a lesser deep petrosal nerve.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus including:

an instrument, adapted to detect an indication of cerebral blood flow(CBF) of a subject, and to generate a signal responsive thereto;

one or more electrodes, adapted to be placed in a vicinity of a site ofthe subject selected from a sphenopalatine ganglion (SPG), a greaterpalatine nerve, a lesser palatine nerve, a sphenopalatine nerve, acommunicating branch between a maxillary nerve and an SPG, an oticganglion, an afferent fiber going into the otic ganglion, an efferentfiber going out of the otic ganglion, an infraorbital nerve, a vidiannerve, a greater superficial petrosal nerve, and a lesser deep petrosalnerve; and

a control unit, adapted to:

receive the signal,

drive the one or more electrodes to apply a current to the site capableof inducing a change in the CBF, and

configure a parameter of the current responsively to the signal.

For some applications, the instrument includes a laser Doppler perfusiondevice, a transcranial Doppler ultrasonography device, a thermometer, ora near infrared spectroscopy (NIRS) device. Alternatively, theinstrument includes an image sensor, adapted to image an eye of thesubject, and the indication of CBF includes an indication ofvasodilation of blood vessels of the eye. For some applications, theindication of vasodilation of the blood vessels of the eye includes aratio of red to white in a sclera of the eye, and the instrument isadapted to determine the ratio.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

placing one or more electrodes in a vicinity of a site of a subjectselected from a sphenopalatine ganglion (SPG), a greater palatine nerve,a lesser palatine nerve, a sphenopalatine nerve, a communicating branchbetween a maxillary nerve and an SPG, an otic ganglion, an afferentfiber going into the otic ganglion, an efferent fiber going out of theotic ganglion, an infraorbital nerve, a vidian nerve, a greatersuperficial petrosal nerve, and a lesser deep petrosal nerve;

applying a current to the site capable of inducing a change in cerebralblood flow (CBF) of the subject;

detecting an indication of the CBF; and

responsively to the indication, adjusting at least one of: a placementof the electrodes, and a parameter of the applied current.

The present invention will be more fully understood from the followingdetailed description of the embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a neural stimulation system, inaccordance with an embodiment of the present invention;

FIG. 2 is a schematic cross-sectional illustration of a spring-loadedlocking element engaging the greater palatine canal, in accordance withan embodiment of the present invention;

FIGS. 3A and 3B are schematic illustrations of a laterally displacedconfiguration of a stimulator of the system of FIG. 1, in accordancewith an embodiment of the present invention;

FIGS. 4A and 4B are schematic illustrations of out-of-planeconfigurations of the stimulator of the system of FIG. 1, in accordancewith respective embodiments of the present invention;

FIGS. 5A-D are schematic illustrations of a longitudinally-orientedconfiguration of the stimulator of the system of FIG. 1, in accordancewith an embodiment of the present invention;

FIGS. 6A-D are schematic illustrations of variable-length supportelements of the system of FIG. 1, in accordance with respectiveembodiments of the present invention;

FIGS. 7A-B are schematic illustrations of an oral element of the systemof FIG. 1, in accordance with respective embodiments of the presentinvention;

FIG. 8 is a schematic illustration of an oral element of the system ofFIG. 1 coupled to an oral appliance, in accordance with an embodiment ofthe present invention;

FIG. 9 is a schematic illustration of a contact-based energytransmission configuration of the system of FIG. 1, in accordance withan embodiment of the present invention;

FIG. 10 is a schematic illustration of a configuration of a contact ofthe configuration of FIG. 9, in accordance with an embodiment of thepresent invention;

FIG. 11A-B are schematic illustrations of energy and data transmissionpaths between components of the system of FIG. 1, in accordance withrespective embodiments of the present invention;

FIG. 12 is a schematic illustration of another neural stimulationsystem, in accordance with an embodiment of the present invention;

FIG. 13 is a schematic illustration of an implantable submucosal antennaof the system of FIG. 12, in accordance with an embodiment of thepresent invention;

FIGS. 14A-B are schematic illustrations of energy and data transmissionpaths between components of the system of FIG. 12, in accordance withrespective embodiments of the present invention;

FIG. 15 is a schematic illustration of a configuration of the stimulatorof the stimulation system of FIGS. 12-14, in accordance with anembodiment of the present invention;

FIG. 16 is a schematic illustration of an electrode configuration, inaccordance with an embodiment of the present invention;

FIGS. 17A-C are schematic illustrations of an array of electrodes, inaccordance with an embodiment of the present invention;

FIG. 18 is a schematic pictorial view of a stimulation system forstimulation of a modulation target site, in accordance with anembodiment of the present invention;

FIG. 19 is a schematic illustration of a vasodilation measurementinstrument, in accordance with an embodiment of the present invention;

FIG. 20 is a schematic illustration of a laser Doppler imaging (LDI)device, in accordance with an embodiment of the present invention;

FIG. 21 is a schematic illustration of a thermometer, in accordance withan embodiment of the present invention; and

FIG. 22 is a schematic illustration of a transcranial Dopplerultrasonography device, in accordance with an embodiment of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 is a schematic illustration of a neural stimulation system 20, inaccordance with an embodiment of the present invention. System 20typically comprises an implantable neural stimulator 30, an oral element32, and an external control unit 34. Stimulator 30 comprises anelongated support element 36, one or more electrodes 38 fixed to thesupport element in a vicinity of a distal end thereof, and circuitry 40coupled to the support element in a vicinity of a proximal end thereof.Circuitry 40 typically comprises a wireless coupling element (whichtypically comprises a coil), and additional elements, such as one ormore rectifiers, capacitors, amplifiers, or filters. One or more leads(not shown in FIG. 1), which pass along, through, or around supportelement 36, couple electrodes 38 to circuitry 40. Alternatively, theleads function as the support element, i.e., the support element doesnot comprise any structural elements in addition to the leads. Furtheralternatively, the leads provide a substantial portion of the structuralsupport of the support element, and the balance of the structuralsupport is provided by other elements. For example, support element 36may comprise the leads and a flexible sleeve surrounding the leads; theleads supply most of the structural support of the support element,while the sleeve allows smooth passage of the leads through the greaterpalatine canal. Circuitry 40 is shown schematically in FIG. 1; severalmore detailed configurations of the circuitry are described hereinbelowwith reference to FIGS. 3A-B, 4A-B, and 5A-D.

Stimulator 30 is adapted to be passed through a greater palatine foramen42 of a hard palate 50 of an oral cavity 52 of a subject into a greaterpalatine canal 54, such that electrodes 38 are brought into a vicinityof a sphenopalatine ganglion (SPG) 56. For some applications, the entirestimulator is contained within greater palatine canal 54, while forother applications, at least a portion of the circuitry and/or thesupport element are positioned submucosally in the oral cavity. Forclarity of illustration, the greater and lesser palatine nerves, and thegreater and less palatine arteries are not shown in the figures. Duringan implantation procedure, stimulator 30 is typically passed throughgreater palatine foramen 42 posterior to the greater palatine nerve andartery, which are manipulated into an anterior position within thecanal.

For some applications, electrodes 38 apply a monophasic waveform to SPG56, while for other applications, electrodes 38 apply a biphasicwaveform. Alternatively or additionally, waveforms and/or stimulationtechniques may be used that are described in one or more of the patentapplications incorporated by reference hereinbelow, or waveforms and/orstimulation techniques may be used that are known in the art of neuralstimulation.

For some applications, the distal end of support element 36 comprises asurgical punch 60, which is adapted to be passed through mucosa 58 andgreater palatine foramen 42 without requiring a prior surgical incisionin the mucosa, i.e., without requiring the use of a surgical knife orother tool. Circuitry 40 is sufficiently small so as to be able to passthrough the punch incision without requiring the incision to besurgically enlarged.

For some applications, stimulator 30 comprises a locking element, suchas in a vicinity of the proximal end thereof, which is adapted to holdthe stimulator in place after insertion. For some applications, thelocking element comprises a screw, which is adapted to couple thestimulator to the palate or the alveolar process of the maxilla.Alternatively or additionally, the locking element comprises a bondingagent, which is adapted to bond the stimulator to the palate, thealveolar process of the maxilla, or an internal surface of greaterpalatine canal 54.

Reference is made to FIG. 2, which is a schematic cross-sectionalillustration of a spring-loaded locking element 62 engaging greaterpalatine canal 54, in accordance with an embodiment of the presentinvention. Locking element 62 applies lateral pressure on the interiorsurface of a portion of greater palatine canal 54 in a vicinity offoramen 42, thereby locking elongated support element 36 in place in thecanal. Locking element 62 is configured so as to not interfere with adescending palatine artery 64 or a greater palatine nerve 66, both ofwhich pass through greater palatine canal 54.

For some applications, support element 36 has a length of between about1.8 and about 3 cm, such as between about 2.6 cm and about 3 cm, e.g.,between about 2.6 and about 3 cm, such as about 2.8 cm, and has acurvature that follows that of the greater palatine canal. For someapplications, support element 36 has a diameter at its widest portion ofbetween about 1 and about 4 mm. For some applications, support element36 comprises a tube. For some applications, support element 36 issemi-rigid (i.e., it generally keeps its original shape during aplacement procedure). For example, support element 36 may besufficiently rigid to enable insertion of the support element into abody of the subject by pushing from a vicinity of a proximal end of thesupport element. For some applications, support element 36 andelectrodes 38 together are similar to conventional concentric needleelectrodes, such as Medtronic, Inc. needle electrode model DCN50, orOxford Instruments Plc. needle electrode models X53153, X53155, X53156,X53158, or X53159.

Each of electrodes 38 typically comprises a suitable conductivematerial, for example, a physiologically-acceptable material such assilver, iridium, platinum, a platinum iridium alloy, titanium, nitinol,or a nickel-chrome alloy. For some applications, each of the electrodeshas a surface area of between about 1 and about 8 mm², such as about2.653 or about 6.123 mm². For some applications, electrodes 38 arerecessed within support element 36, while for other applications theelectrodes are flush with the surface of the support element, orprotrude therefrom. Electrodes 38 are insulated from one another with aphysiologically-acceptable material such as polyethylene, polyurethane,or a co-polymer of either of these. For some applications, theelectrodes are spiral in shape, for better contact, and may have a hookshaped distal end for hooking into or near the SPG. Alternatively oradditionally, the electrodes may comprise simple wire electrodes,spring-loaded “crocodile” electrodes, or adhesive probes, asappropriate. For some applications, the electrodes are coated with abiocompatible material configured to enhance the surface area of theelectrodes, thereby increasing the capacitance and reducing theresistance of the electrodes. For example, the material may comprise aplatinum/iridium alloy, and/or may be applied with a sputtering process,such as commercially available from Johnson Matthey Plc, Advanced MetalsTechnology division (London, UK).

Optionally, support element 36 comprises one or more marks (not shown)that indicate the depth of insertion of stimulator 30 into greaterpalatine canal 54. Alternatively or additionally, for some applicationssupport element 36 comprises a stopper (not shown) in a vicinity of themarks, that mechanically prevents insertion of the support element intothe canal beyond a certain depth.

Reference is made to FIGS. 3A-B, 4A-B, and 5A-D, which are schematicillustrations of several configurations of stimulator 30, in accordancewith respective embodiments of the present invention. In theseembodiments, stimulator 30 comprises a circuit module 41, whichcomprises circuitry 40 coupled to a printed circuit board. Circuitmodule 41 has a generally flat shape, typically with a thickness of lessthan about 2 mm, such as less than about 1.2 mm, e.g., about 1.05 mm.For some applications, one or more layers of coating are applied tocircuit module 41, such as in order to provide a conforming, thin,smooth, watertight, biocompatible, and/or mechanically-protectivesurface. For example, a first, innermost coating may comprise an inertbiocompatible polymer, such as Parylene C, having a thickness of betweenabout 10 and about 15 microns. A second watertight mineral-basedsealant, such as Al₂O₃, SiO₂, or Si₂N₃, may be applied over theinnermost coating by sputtering. The thickness of the watertight sealantis typically between about 1 and about 2 microns. A third, outermostcoating of an inert biocompatible polymer, such as Parylene C, having athickness of between about 10 and about 15 microns, may be applied overthe watertight sealant.

FIGS. 3A and 3B are schematic illustrations of a laterally displacedconfiguration of stimulator 30, in accordance with an embodiment of thepresent invention. FIG. 3A shows stimulator 30 in an unfolded position.Circuit module 41 has a generally flat shape, and may be generallyelliptical, as shown in FIG. 3A, or may have another shape, such asrectangular. Prior to insertion in greater palatine canal 54, supportelement 36 is folded at a fold 44 at an angle α approximately equal tothe angle between greater palatine canal 54 and hard palate 50 in avicinity of foramen 42. During an implantation procedure, (a) asubmucosal surface on the hard palate is prepared, such as by raising amucosal flap, by creating a mucosal opening using a retractor, and/or bypreparing a submucosal pocket using a tool which has generally the sameshape and dimensions as circuit module 41, (b) support element 36 isinserted into greater palatine canal 54, (c) circuit module 41 is placedagainst the exposed lower surface of hard palate 50, and (d) mucosa 58is closed over circuit module 41 and the portion of support element thatprotrudes from greater palatine canal 54. For implantation proceduresduring which a mucosal flap is raised, an approximately 3 cm incision istypically required to raise the mucosal flap. For some applications, thecircuit module is coupled to the hard palate, such as by using at leastone nail or screw (coupling not shown). Typically, the distal portion ofsupport element 36 beyond fold 44 has a length L1 of between about 26and about 30 mm, e.g., about 28 mm, and the entire stimulator 30 in anunfolded position, including circuit module 41, has a length L2 ofbetween about 40 and about 44 mm, e.g., about 42 mm.

FIGS. 4A and 4B are schematic illustrations of out-of-planeconfigurations of stimulator 30, in accordance with respectiveembodiments of the present invention. In these configurations, aproximal end 46 of support element 36 is coupled directly to circuitmodule 41, such that an angle β between support element 36 and thesurface of circuit module 41 is approximately equal to the angle betweengreater palatine canal 54 and hard palate 50 in a vicinity of foramen42. As in the configuration shown in FIGS. 3A and 3B, circuit module 41has a generally flat shape, and may be generally elliptical, or may haveanother shape, such as rectangular. In the configuration shown in FIG.4A, proximal end 46 of support element 36 is coupled to circuit module41 in a vicinity of a center of the surface of the circuit module. Forsome applications, the circuit module is coupled to the support elementsuch that the longer axis or side of the circuit module is oriented inan anterior-posterior direction. Alternatively, the longer axis or sideof the circuit module is oriented in a left-right direction, or inanother direction. Typically, support element 36 has a length of betweenabout 26 and about 30 mm, e.g., about 28 mm.

In the configuration shown in FIG. 4B, proximal end 46 is coupled tocircuit module in a vicinity of an edge of the surface of the circuitmodule. The support element may be coupled to any point on the edge,e.g., in a vicinity of an end of a major axis or a minor axis of thecircuit module. For some applications, proximal end 46 of supportelement 36 is coupled to circuit module 41 at a location between thecenter of the circuit module and the edge of the circuit module. Forsome applications, the circuit module is coupled to the support elementsuch that the circuit module extends in an anterior direction, in aposterior direction, towards the center of the mouth, or towards themaxillary bone. For example, when the circuit module extends in aposterior direction or towards the center of the mouth, the circuitmodule is less likely to interfere with branches of the greater palatinenerve or greater palatine artery that extend in an anterior directionfrom greater palatine foramen 42. For some applications, circuit module41 is generally kidney-shaped.

During an implantation procedure, (a) a submucosal surface on the hardpalate is prepared, such as by raising a mucosal flap, by creating amucosal opening using a retractor, and/or by preparing a submucosalpocket using a tool which has generally the same shape and dimensions ascircuit module 41, (b) support element 36 is inserted into greaterpalatine canal 54, (c) circuit module 41 is placed against the exposedlower surface of hard palate 50, and (d) mucosa 58 is closed overcircuit module 41. For implantation procedures during which a mucosalflap is raised, an approximately 7 mm incision is typically required toraise the mucosal flap. For some applications, the circuit module iscoupled to the hard palate, such as by using at least one nail or screw(coupling not shown).

FIGS. 5A-D are schematic illustrations of a longitudinally-orientedconfiguration of stimulator 30, in accordance with an embodiment of thepresent invention. In this configuration, a proximal end 46 of supportelement 36 is coupled to circuit module 41. Circuit module 41 has agenerally flat shape, and may be generally elliptical, as shown in FIG.5A, or may have another shape, such as rectangular. As shown in FIGS.5B-D, a proximal portion 48 of support element 36 which protrudes fromgreater palatine canal 54 is sufficiently flexible to follow the contourof the palate and alveolar process.

During an implantation procedure, (a) a submucosal surface on the hardpalate is prepared, such as by raising a mucosal flap, by creating amucosal opening using a retractor, and/or by preparing a submucosalpocket using a tool which has generally the same shape and dimensions ascircuit module 41, (b) support element 36 is inserted into greaterpalatine canal 54, (c) circuit module 41 is placed against an alveolarprocess 68 of the maxilla, and (d) mucosa 58 is closed over circuitmodule 41. For implantation procedures during which a mucosal flap israised, an approximately 5 mm incision is typically required to raisethe mucosal flap. For some applications, the circuit module is coupledto the alveolar process, such as by using at least one nail or screw(coupling not shown).

Reference is made to FIGS. 6A-D, which are schematic illustrations ofvariable-length support elements 36, in accordance with respectiveembodiments of the present invention. In these embodiments, the lengthof support element 36 is adjustable during the implantation procedure,in order to accommodate differing lengths of greater palatine canal 54.It is noted that the variation in the length of the greater palatinecanal in adults is generally less than +/−2 mm, so the length of supportelements 36 in these embodiment need only vary by a relatively smallpercentage.

In the configuration shown in FIG. 6A, support element 36 is configuredto allow telescopic coupling of a portion 80 of the support element.Electrode leads 84 pass through support element 36, including portion80. The leads have sufficient slack so as to not interfere with theexpansion and contraction of telescopic portion 80.

In the configuration shown in FIG. 6B, a portion of support element 36is shaped so as to define one or more accordion pleats 82. Accordionpleats 82 are typically biased such that they are generally extendedwhen in a relaxed position. Electrode leads 84 pass through supportelement 36, including the accordion portion. The leads have sufficientslack so as to not interfere with the expansion and contraction ofaccordion pleats 82. For some applications, support element 36 comprisesa sleeve 88, which surrounds accordion pleats 82. The sleeve typicallyhas a length no greater than the length of support element 36 when thesupport element is in its most contracted position, i.e., the sleevesurrounds only a portion of the non-accordion-pleated portion of theelectrode leads. Such a length allows the total length of the supportelement to vary without being constrained by the length of the sleeve.Sleeve 88 typically comprises a flexible, biocompatible material, suchas silicone. Sleeve 88 typically has a length less than 28 mm, e.g.,less than 26 mm. Alternatively, for some applications, electrode leads84 are accordion-pleated, in which case the electrode leads serve assupport element 36.

In the configuration shown in FIG. 6C, electrode leads 84 are helicallywound, so as to form a spring 86. The spring is typically biased so asto have an expanded resting position. For some applications, supportelement 36 comprises sleeve 88, which surrounds spring 86. The sleevetypically has a length no greater than the length of support element 36when the support element is in its most contracted position, i.e., thesleeve surrounds only a portion of the non-helically-wound portion ofthe electrode leads. Such a length allows the total length of thesupport element to vary without being constrained by the length of thesleeve.

In the configuration in FIG. 6D, electrode leads 84 are shaped to as todefine at least one omega-shaped portion 90. Portion 90 is typicallybiased so as to have extended resting positions. For some applications,support element 36 comprises sleeve 88, as described above withreference to FIGS. 6B and 6C.

Reference is made to FIGS. 7A-B, which are schematic illustration oforal element 32, in accordance with respective embodiments of thepresent invention. Oral element 32 is adapted to be placed in oralcavity 52 in a vicinity of implanted circuitry 40 of stimulator 30,e.g., in a vicinity of or in contact with the roof of the oral cavity.Oral element 32 typically comprises a power source 72, such as arechargeable or disposable battery, circuitry 73, and at least onewireless coupling element 74. Depending on the specific application,wireless coupling element 74 transmits energy and/or data to circuitry40, as described hereinbelow. For some applications, wireless couplingelement 74 comprises a relatively large coil or a plurality of smallercoils, which may increase the likelihood that at least some portion ofthe generated magnetic field achieves good wireless coupling withimplanted circuitry 40 of stimulator 30, even if oral element 32 is notprecisely positioned or aligned with respect to stimulator 30, or iforal element 32 moves slightly after it has been placed against the roofof the oral cavity. For some applications in which wireless couplingelement 74 comprises a plurality of coils, the coils are oriented withrespect to one another such that the respective axes of the coils arenot parallel with one another. For example, the coils may be orientedsuch that two or three of the axes are approximately orthogonal with oneanother.

In the embodiment shown in FIG. 7A, oral element 32 is adapted to betemporarily placed in oral cavity 52, without mechanically coupling theoral element to a surface of the oral cavity. For some applications,oral element 32 is coupled to an oral appliance, as describedhereinbelow with reference to FIG. 8. In the embodiment shown in FIG.7B, oral element 32 is adapted to be fixed to the roof of oral cavity52, such as by using one or more screws 70, nails, or other surgicalfastening devices.

FIG. 8 is a schematic illustration of oral element 32 coupled to an oralappliance 92, in accordance with an embodiment of the present invention.Oral appliance 92, which is typically shaped generally similarly to anorthodontic retainer, is configured to hold the oral element in avicinity of or in contact with the roof of the oral cavity in a vicinityof implanted circuitry 40 of stimulator 30. The use of oral appliance92, rather than mechanical coupling of oral element 32 to the roof ofthe oral cavity, generally reduces the likelihood of contamination. Forsome applications, oral appliance 92 is generally soft or semi-flexible,while for other applications, the oral appliance is generally rigid.

For some applications, oral element 32 does not comprise power source72. Instead, power is provided by a power source located outside of theoral cavity. For example, the oral appliance may be coupled by a cableto an external driver comprising a power source. For some applications,the driver is coupled to a headset or necklace worn by the subject. Thedriver or a separate external control unit, instead of oral element 32,comprises all or a portion of circuitry 73. For some applications, thedriver is coupled to external control unit 34, while for otherapplications, the driver comprises external control unit 34.Alternatively, oral element 32 is wirelessly coupled to external controlunit 34, which may or may not be coupled to the external driver.

Reference is again made to FIGS. 5B-D. In the embodiment of the presentinvention shown in FIG. 5B, oral element 32 is configured to be coupledto a molar 98 or other tooth of the subject. For example, the oralelement may comprise a clip or adhesive. Typically, the oral element isconfigured to be removably coupled to the tooth. For example, the oralelement may be coupled to the tooth only during applications ofstimulation by stimulator 30, and removed between applications ofstimulation.

In the embodiment shown in FIG. 5C, oral element 32 is configured to becoupled to gingiva 99 covering alveolar process 68, and, optionally, toone or more teeth. For some applications, the oral element 32 is coupledto gingival 99 using a clamp 101. Alternatively or additionally, theoral element is adapted to be held in place by the subject biting downon the element.

In the embodiment shown in FIG. 5D, oral element 32 comprises a capsule200, which, for some applications, comprises power source 72 andcircuitry 73. Oral element 32 further comprises an elongated connectingelement 202, which couples capsule 200 to wireless coupling element 74.Capsule 200 is configured to be placed and held between alveolar process68 and the inner surface of a cheek 204. For some applications, capsule200 is generally cylindrical, similar in shape and size to aconventional dental cotton roll. Optionally, the capsule comprises asoft coating. Oral element 32 is configured such that wireless couplingelement 74 is positioned on the lingual side of the teeth. For someapplications, connecting element 202 passes over the occlusal surface ofone or more teeth, as shown in FIG. 5D, while for other applications,connecting element 202 passes around the distal surface of the mostdistal molar (configuration not shown). Alternatively, connectingelement 202 serves as wireless coupling element 74.

For some applications, capsule 200 does not comprise power source 72.Instead, power is provided by a power source located outside of the oralcavity. For example, the capsule may be coupled by a cable to anexternal driver comprising a power source. For some applications, thedriver is coupled to a headset or necklace worn by the subject. Thedriver or a separate external control unit, instead of capsule 200,comprises all or a portion of circuitry 73. For some applications, thedriver is coupled to external control unit 34, while for otherapplications, the driver comprises external control unit 34.

In an embodiment of the present invention, system 20 comprises a nasalelement instead of or in addition to oral element 32 (configuration notshown). The nasal element is adapted to be inserted into a nostril ofthe subject, e.g., into the nasal vestibule. The nasal element comprisesat least one wireless coupling element 74 that is wirelessly coupled totransmit/receiver 40 of stimulator 30, for transmitting/receiving powerand/or data to/from the stimulator. In this embodiment, circuitry 40 ofstimulator 30 is not necessarily positioned at the proximal end of thestimulator.

For some applications, circuitry 40 of stimulator 30 comprises awireless coupling element. Wireless coupling element 74 of oral element32 is adapted to wirelessly transmit energy and/or data to the wirelesscoupling element of circuitry 40, and/or to wirelessly receive data formthe wireless coupling element of circuitry 40. For these applications,each of the wireless coupling elements typically comprises at least onecoil. For some applications, the wireless coupling elements arewirelessly coupled to one another using induction, such as when thewireless coupling elements are positioned in close proximity to oneanother. Alternatively, the wireless coupling elements are wirelesslycoupled to one another using RF energy, such as when the wirelesscoupling elements are positioned at a greater distance from each other.Further alternatively, the wireless coupling elements are wirelesslycoupled to one another using another form of energy, such as ultrasoundenergy, in which case the wireless coupling elements comprisesultrasound transducers, e.g., piezoelectric transducers. “Transducerelement,” as used in the present application including the claims, meansan element adapted to wirelessly transmit and/or receive energy and/ordata, including a coil, a piezoelectric transducer, and other wirelesstransducers known in the art.

In an embodiment of the present invention, oral element 32 does notcomprise wireless coupling element 74. Instead, power source 72 of theoral element is coupled to circuitry 40 using a wire that passes throughmucosa 58. The techniques of this embodiment are generally moreenergy-efficient than wireless energy/data transfer techniques. As aresult, the battery of power source 72 of oral element 32 may need to bereplaced or recharged less frequently, or not at all. For someapplications, oral element 32 is adapted to be implanted in a tooth ofthe subject. For some applications, the implanted oral element comprisesa wireless communication element for external wireless communication,such as of data. For some applications, power source 72 comprises arechargeable or a replaceable battery.

Reference is made to FIG. 9, which is a schematic illustration of acontact-based energy transmission configuration of stimulation system20, in accordance with an embodiment of the present invention. In thisembodiment, a proximal end of support element 36 of stimulator 30comprises a contact 94 that protrudes slightly from mucosa 58. Oralelement 32 comprises a contact 96, which is brought into physicalcontact with contact 94 for transmitting power and/or data to/fromcircuitry 40. Contact 94 of stimulator 30 is typically in sealed contactwith mucosa 58, in a similar manner to pacemaker leads. For someapplications, contact 94 is typically semi-spherical in shape, as shownin FIG. 9. Alternatively, contact 94 is generally flat or concave inshape. The use of the contact-based techniques of this embodiment doesnot require alignment of oral element 32 with circuitry 40. In addition,the contact-based techniques of this embodiment result in a uniform,predictable transfer of energy, and are generally more energy-efficientthan wireless energy/data transfer techniques. As a result, the batteryof power source 72 of oral element 32 may need to be replaced orrecharged less frequently, or not at all.

FIG. 10 is a schematic illustration of a configuration of contact 94, inaccordance with an embodiment of the present invention. In thisembodiment, contact 94 comprises positive and negative terminals 95 and96, each of which is coupled to a respective lead 84. For someapplications, support element 36, at a portion thereof which passesthrough mucosa 58, comprises a matrix 97, which is adapted to promotemucosal tissue growth therein. The growth of mucosal tissue in thematrix generally reduces the likelihood of infection, and helps holdcontact 94 in place. For some applications, contact 94 and/or matrix 97is coated with an antiseptic substance, such as an antibacterialsubstance, to reduce the likelihood of infection passing from the oralcavity through the mucosa.

Reference is made to FIG. 11A, which is a schematic illustration ofenergy and data transmission paths between components of system 20, inaccordance with an embodiment of the present invention. Typically,wireless coupling element 74 of oral element 32 is adapted to wirelesslytransmit energy to circuitry 40 of stimulator 30, for powering thestimulator, as symbolically indicated by an arrow 100. The closeproximity of the wireless coupling elements of oral element 32 andstimulator 30 generally allows the use of relatively low energy levelsand/or a small receiving element in circuitry 40, e.g., a small coil orpiezoelectric transducer.

In an embodiment of the present invention, the energy transmitted tocircuitry 40 of stimulator 30 does not include the stimulation waveformto be applied using electrodes 38. Instead, energy is typicallytransferred using a continuous wave (i.e., electromagnetic energy ofconstant amplitude and frequency). Circuitry 40 of stimulator 30 isconfigured to generate the stimulation waveform applied by electrodes38. Alternatively, the energy is transferred using a quasi-continuouswave, which encodes data, which data is used by circuitry to generatethe stimulation waveform applied by electrodes 38. The techniques ofthis embodiment may be employed, for example, with the configurations ofstimulation system 20 described hereinabove with reference to FIGS. 1and/or 8, and/or hereinbelow with reference to FIGS. 12-14 and/or 15.The transfer of energy only, in accordance with this embodiment,generally allows complete control of the waveform delivered byelectrodes 38, because the generation of the waveform is independent ofthe wireless coupling of oral element 32 and circuitry 40 of stimulator30. Furthermore, for some applications, circuitry 40 generates a bipolarwaveform, which typically reduces the total accumulated charge in thetissue, thus improving safety and electrode life span.

For some applications, wireless coupling element 74 of oral element 32is additionally configured to transmit and/or receive data to/fromcircuitry 40 of stimulator 30, as indicated by an arrow 102. Such datatypically includes stimulation control signals, parameters, and/orfeedback information. Such data is typically transmitted onlyperiodically, rather than constantly during stimulation. Circuitry 40 ofstimulator 30 configures at least a portion of the stimulationparameters based on the received information. For these applications,circuitry 40 of stimulator 30 is configured to generate the stimulationwaveform applied by electrodes 38, based on the configured parameters.

For some applications, wireless coupling element 74 of oral element 32(either the same wireless coupling element used for transmitting andreceiving data to and from circuitry 40 of stimulator 30, or a separatewireless coupling element) is adapted to wirelessly relay the data toand receive data from external control unit 34 (as indicated by an arrow104), which also comprises a wireless coupling element 106. Typically,but not necessarily, substantive processing and generation of the datais performed exclusively by external control unit 34, rather than byoral element 32. For some applications, wireless coupling element 74combines the data and the energy transmitted to circuitry 40 ofstimulator 30 into a single signal, such as by modulating the data ontothe carrier frequency of the transmitted energy, in which case circuitry40 demodulates the received signal to obtain the data. Alternatively,wireless coupling element 74 transmits the data and the energy inseparate signals. Alternatively, for some applications, circuitry 40 ofstimulator 30 is configured to transmit and/or receive all or a portionof the data directly to/from external control unit 34 (as indicated byan arrow 108), bypassing oral element 32, such as by using a VHF signal.

For some applications in which the energy is transferred using acontinuous wave, the energy is transferred from outside the body of thesubject, e.g., from a vicinity of the cheek or ear of the subject,rather than from oral element 32. This is possible because thecontinuous wave generally has low peak power levels. For theseapplications, system 20 typically does not comprise oral element 32.

In an embodiment of the present invention, circuitry 73 of oral element32 generates the stimulation waveform, and wirelessly transmits thewaveform to circuitry 40 of stimulator 30. For these applications,circuitry 40 of stimulator 30 is generally passive, and simply relaysthe received waveform to electrodes 38 with minimal or no processing.Circuitry 40 typically comprises a simple circuit, including one or morerectifiers and capacitors. The techniques of this embodiment may beemployed, for example, with the configurations of stimulation system 20described hereinabove with reference to FIGS. 1, 8, and/or 9.

For some applications, system 20 is configured to perform a calibrationprocedure in which the absolute energy level of the applied waveform isdetermined, and adjusted appropriately to achieve a desired stimulationlevel. Such calibration compensates for the patient-to-patientvariability in energy transfer, caused, for example, by differences inplacement and/or orientation of oral element 32 or circuitry 40 ofstimulator 40, and/or inter-patient anatomical differences, e.g.,thickness of the mucosa.

Reference is made to FIG. 11B, which is a schematic illustration ofenergy and data transmission paths between components of system 20, inaccordance with an embodiment of the present invention. Except asdescribed hereinbelow, this embodiment is similar to the embodimentdescribed hereinabove with reference to FIG. 11A. In this embodiment,system 20 additionally comprises an external driver 110, which comprisespower source 72 and circuitry 73. Oral element 32 comprises wirelesscoupling element 74, but typically does not comprise power source 72 orcircuitry 73 (the oral element and/or the wireless coupling element maycomprise minimal circuitry, such as one or more rectifiers orcapacitors). Oral element 32 is electrically coupled to external driver110 by an elongated flexible coupling element 112, which comprises oneor more wires. Driver 110 is typically adapted to be physically coupledto a body of the subject, such as by being coupled to headset or anecklace.

Driver 110 typically comprises a wireless coupling element 114, whichthe driver uses to wirelessly relay data to and receive data fromexternal control unit 34 (as indicated by an arrow 116). For example,the data may be transmitted using the Bluetooth protocol or anotherwireless communication protocol, or using an infrared signal.Alternatively, driver 110 is coupled to external control unit 34 by oneor more wires (configuration not shown).

Reference is made to FIG. 12, which is a schematic illustration of aneural stimulation system 120, in accordance with an embodiment of thepresent invention. Except as noted hereinbelow, elements of system 120are the same as corresponding elements of system 20 having the samereference numerals. System 120 comprises implantable neural stimulator30 and external control unit 34. Stimulator 30 comprises elongatedsupport element 36, one or more electrodes 38 fixed to the supportelement in the vicinity of the distal end thereof, and an implantablesubmucosal antenna 122 coupled to the support element in a vicinity ofthe proximal end thereof. Submucosal antenna 122 is adapted to beimplanted in the roof of oral cavity 52 between oral mucosa 58 and apalate, e.g., hard palate 50 and/or a soft palate 134, and to generallyconform to the shape of the palate.

FIG. 13 is a schematic illustration of implantable submucosal antenna122, in accordance with an embodiment of the present invention.Submucosal antenna 122 comprises a thin, flexible sheet 124, whichcomprises at least one coil 126. Sheet 124 comprises a flexiblebiocompatible material, such as silicone.

Reference is made to FIG. 14A, which is a schematic illustration ofenergy and data transmission paths between components of system 120, inaccordance with an embodiment of the present invention. System 120typically lacks oral element 32 of system 20. Instead, external control34 unit is adapted to transmit power, typically using RF energy,directly to submucosal antenna 122, for powering stimulator 30, asindicated by an arrow 140, and to transmit and/or receive data directlyto/from the submucosal antenna, as indicated by an arrow 142. Such datatypically includes stimulation control signals, parameters, and/orfeedback information. Such data is typically transmitted onlyperiodically, rather than constantly during stimulation. Circuitry 40 ofstimulator 30 is configured to generate the stimulation waveform appliedby electrodes 38, based on the configured parameters.

For some applications, wireless coupling element 106 combines the dataand the energy into a single signal, such as by modulating the data ontothe carrier frequency of the transmitted energy, in which casesubmucosal antenna 122 demodulates the received signal to obtain thedata. Alternatively, wireless coupling element 106 transmits the dataand the energy in separate signals. Alternatively, for someapplications, stimulator 30 additionally comprises a wireless couplingelement 144, to/from which external control unit 34 transmits and/orreceives data, such as by using a VHF signal. Typically, externalcontrol unit 34 is adapted to be placed in a vicinity of a head of thesubject, such as in a vicinity of an ear of the subject. For someapplications, external control unit 34 is adapted to be coupled to theear. For example, the control unit may comprise or be integrated into awired or wireless headset, such as a cellular phone headset.

Reference is made to FIG. 14B, which is a schematic illustration ofenergy and data transmission paths between components of system 120, inaccordance with an embodiment of the present invention. Except asdescribed hereinbelow, this embodiment is similar to the embodimentdescribed hereinabove with reference to FIG. 14A. In this embodiment,system 120 additionally comprises external driver 110, which comprisespower source 72, circuitry 73, and at least one wireless couplingelement 128. Driver 110 is typically adapted to be worn by the subject,such as by being coupled to headset or a necklace. Driver 110 is adaptedto use wireless coupling element 128 to transmit power, typically usingRF energy, directly to submucosal antenna 122, for powering stimulator30, as indicated by an arrow 140, and to transmit and/or receive datadirectly to/from the submucosal antenna, as indicated by an arrow 142.

Driver 110 typically uses wireless coupling element 128, or a separatewireless coupling element (not shown), to wirelessly relay data to andreceive data from external control unit 34 (as indicated by an arrow130). For example, the data may be transmitted using the Bluetoothprotocol or another wireless communication protocol, or using aninfrared signal. Alternatively, driver 110 is coupled to externalcontrol unit 34 by one or more wires (configuration not shown).

Reference is made to FIG. 15, which is a schematic illustration of aconfiguration of stimulator 30 for use in stimulation system 120,described hereinabove with reference to FIGS. 12-14, in accordance withan embodiment of the present invention. In this embodiment, instead ofsubmucosal antenna 122, system 120 comprises a coil antenna 160, atleast a portion of which is coiled around at least a portion 162 ofsupport element 36. Alternatively, coil antenna 160 is an integral partof portion 162. For some applications, coil antenna 160 comprisesferrite. For some applications, a sleeve is placed around all or aportion of coil antenna 160 and/or support element 36 (configuration notshown). Typically, the distal end of support element 36 comprisessurgical punch 60, described hereinabove with reference to FIG. 1. Forsome applications, coil antenna 160 comprises a plurality of coilsarranged in various orientations, which generally improves wirelesscoupling with wireless coupling element 106 of external control unit 34.For example, the plurality of coils may comprise two or three coilsoriented approximately orthogonally to one another. In the configurationshown in FIG. 15, support element 36 and coil antenna 160 are typicallyadapted to be contained entirely within greater palatine canal 54.

Reference is made to FIG. 16, which is a schematic illustration of aconfiguration of electrodes 38, in accordance with an embodiment of thepresent invention. In this embodiment, electrodes 38 comprise at leastone (e.g., exactly one) cathode 150, and at least one (e.g., exactlyone) anode 152. Cathode 150 is typically located closer to a distal tip154 of support element 36 than is anode 152. Typically, a length L1 ofanode 152 is greater than a length L2 of cathode 150, such as at least200% of length L2. A closest distance D1 between cathode 150 and anode152 is typically greater than a closest distance D2 between any portionof cathode 150 and any portion of SPG 56.

In an embodiment of the present invention, a method for implantingstimulator 30 in greater palatine canal 54 comprises placing thestimulator in a bore of a needle having a sharp distal tip, passing theneedle through mucosa 58 and greater palatine foramen 42, into canal 54,and withdrawing the needle, thereby leaving the stimulator implanted inthe canal. Alternatively, the needle is first passed into canal 54, andstimulator 30 is subsequently introduced into the bore of the needle.The needle is typically passed through mucosa 58 without requiring aprior surgical incision in the mucosa, i.e., without requiring the useof a surgical knife or other tool. Alternatively, prior to insertion ofthe needle into the canal, a submucosal surface on the hard palate isprepared, such as by raising a mucosal flap, and/or by creating amucosal opening using a retractor.

Reference is made to FIGS. 17A-C, which are schematic illustrations ofan array 190 of electrodes 38, in accordance with an embodiment of thepresent invention. In this embodiment, stimulator 30 of system 20 or 120comprises array 190, which typically comprises between about 8 and about32 electrodes 38, such as about 32 electrodes. FIG. 17A shows array 190in a flat, unrolled position. Typically, the array is organized in rowsand columns, for example, between about 2 and about 8 rows, e.g., 8rows, and between about 2 and about 4 columns, e.g., 4 columns. FIG. 17Bshows array 190 encircling support element 36 (only a single column ofelectrodes 38 is visible in the figure). (For the sake of illustration,support element 36 is visible between electrodes 38 in FIG. 17B; inactual applications, a portion of the support element may be concealedby structural elements of array 190.) FIG. 17C is a cross-sectionaltop-view of one row of electrodes 38. For some applications, array 190is fabricated on a flat substrate 192 (FIG. 17A), which is wrappedaround support element 36 (FIG. 17B). For some applications, substrate192 extends longitudinally along all or a portion of the length ofsupport element 36, electrodes 38 are positioned in a distal region ofthe substrate, and circuitry of stimulator 30, such as circuitry 40,amplifier, and/or filters, is affixed to the substrate, e.g., in aproximal region of the substrate. For other applications, stimulator 30does not comprise substrate 192, and electrodes 38 are coupled directlyto, or are integral with, support element 36. It is noted that althoughstimulator 30 is generally shown in the figures as comprising array 150of electrodes 38, this is for the sake of illustration only; embodimentsdescribed and shown herein may use the electrode configuration describedhereinabove with reference to FIG. 16; electrode configurationsdescribed in U.S. patent application Ser. No. 10/783,113, such as withreference to FIG. 12, 13, or 14 thereof; electrode configurationsdescribed in the other patent applications incorporated by referencehereinbelow; or electrode configurations known in the art of neuralstimulation.

In an embodiment of the present invention, stimulator 30 comprises aplurality of electrodes, at least a portion of which are adapted to beseparately activatable. System 20 or 120 is adapted to use a calibrationalgorithm to activate, during a plurality of calibration periods,respective different sets of one or more of electrodes 38, in order todetermine which set's activation causes a level of stimulation of theSPG closest to a desired level. For example, the desired level may bethe maximum level that can be achieved for a given set of stimulationparameters. For some applications, the algorithm is alternatively oradditionally used for setting a level of one or more stimulationparameters. System 20 or 120 typically uses the algorithm to determinethe optimum set of electrodes after stimulator 30 has been implanted, soas to obviate the need to adjust the location of the stimulator after ithas been implanted. Alternatively or additionally, the position ofstimulator 30 is adjusted responsively to information derived using thealgorithm. For some applications, during post-calibration (i.e.,therapeutic) stimulation, the system activates different sets ofelectrodes at different times, such as in order to vary the level ofstimulation applied to the SPG.

In an embodiment of the present invention, the level of stimulation ofthe SPG is determined by receiving feedback directly from the SPG, orfrom other neural tissue in a vicinity of the SPG, i.e., by using atleast a portion of electrodes 38 to directly measure a level ofstimulation of the SPG or the other neural tissue at or in a vicinity ofthe site(s) of the stimulation by the electrodes. For some applications,the at least a portion of electrodes 38 measure an electrical field ofnervous tissue of the SPG or the other neural tissue induced by theelectrical stimulation of the SPG. Typically, the signal generated bythe sensed field is filtered to remove any artifacts in the signalgenerated by the stimulation applied by electrodes 38.

For some applications, the same set of one or more electrodes appliesstimulation and measures the achieved stimulation of the SPG, bymeasuring the level of stimulation of the SPG or the other neuraltissue. For other applications, a first set of one or more electrodesapplies the stimulation, and a second set of one or more electrodesmeasures the achieved stimulation. Typically, the second set ofelectrodes is located in a vicinity of the first set of electrodes,and/or adjacent to the first set of electrodes in array 190.

Alternatively or additionally, for some applications, the level ofstimulation of the SPG is determined by assessing an indirectphysiological parameter of the subject related to the level of SPGstimulation, such as cerebral blood flow (CBF) and/or BBB permeability.For some applications, assessment techniques described hereinbelow areused. For some applications, a healthcare worker enters the values ofthe indirect physiological parameter into system 20, while for otherapplications, a device for measuring the indirect physiologicalparameters is coupled to system 20, and communicates the parameters tothe system.

For some applications, system 20 is configured to select the desired setof electrodes 38. Alternatively or additionally, system 20 comprises anoutput unit, such as a display, which presents the results of thecalibration algorithm to a healthcare worker, who selects the desiredset of electrodes.

In an embodiment of the present invention, stimulator 30 isautonomically powered, such as by utilizing temperature differentialswithin the subject, e.g., using techniques described in theabove-mentioned U.S. Pat. Nos. 6,470,212 to Weijand et al. and 6,640,137to MacDonald, mutatis mutandis, or other techniques known in the art forgenerating energy from biological processes for powering an implantedmedical device. For some applications, circuitry 40 of stimulator 30does not comprise a wireless coupling element, or the wireless couplingelement is used only for data transmission, rather than for wirelesslyreceiving energy. In the latter case, data is typically transmitted fromand/or to external control unit 34.

In an embodiment of the present invention, electrodes 38 are located ina vicinity of a proximal end of support element 36, such that theelectrodes apply electrical stimulation to greater palatine nerve 66 ina vicinity of the proximal opening of greater palatine foramen 42. Forexample, a closest distance between the electrodes and the proximalopening of the greater palatine foramen may be less than 10 mm, e.g.,less than 5 mm. For some applications, upon implantation of stimulator30, electrodes 38 are contained entirely within greater palatine canal54, while for other applications, all or a portion of the electrodes arelocated submucosally outside of the canal and the foramen.

Although electrodes 38 have been described as being applied to an SPG ofthe subject, for some applications the electrodes are applied to anotherMTS of the subject, as defined hereinabove. For some of theseapplications, electrodes 38 are passed through the greater palatinecanal to the MTS, while for other applications the electrodes are passedthrough only a portion of the greater palatine canal, or are advanced tothe MTS by another route.

FIG. 18 a schematic pictorial view of a stimulation system 500, forstimulation of a sphenopalatine ganglion (SPG) system, as definedhereinabove, and/or at least one other appropriate “modulation targetsite” (MTS), as defined hereinabove, such as SPG 56, in accordance withan embodiment of the present invention. Stimulation system 500 comprisesa support element 510, which typically, but not necessarily, isgenerally rigid (i.e., it generally keeps its original shape during aplacement procedure). A distal end 512 of support element 510 comprisesone or more electrodes 514. For some applications, electrodes 514 arerecessed within support element 510, as shown in the figure, while forother applications the electrodes are flush with the surface of thesupport element, or protrude therefrom. Alternatively, the electrodesare configured as shown in FIGS. 13 and 14 of U.S. patent applicationSer. No. 10/783,113.

Support element 510 is adapted to be inserted into a vicinity of an MTSor an SPG system of the subject, as defined hereinbelow, via a greaterpalatine canal in a roof of an oral cavity of the subject. Typically,support element 510 is substantially straight. Support element 510typically comprises one or more marks 516 that indicate the point atwhich the support element has been sufficiently inserted into thegreater palatine canal. Alternatively or additionally, support element510 comprises a stopper (not shown) in a vicinity of marks 516, thatmechanically prevents further insertion of the support element into thecanal.

Stimulation system 500 further comprises a semi-flexible oral appliance518, which is physically coupled to support element 510 by flexibleleads 520. Oral appliance 518 comprises a neurostimulator 522, which iselectrically coupled to electrodes 514 via leads 520. An upper surface524 of oral appliance 518 is shaped to fit closely to the roof of theoral cavity, and is adapted to be coupled thereto. For example, oralappliance 518 may be shaped generally similarly to an orthodonticretainer. Neurostimulator 522 is typically battery-powered, andconfigurable to drive electrodes 514 to stimulate the MTS or SPG system.For some applications, the subject himself activates neurostimulator522. Stimulation system 500 is typically adapted to remain in the oralcavity for between several hours and about two days.

In an embodiment of the present invention, a stimulation system forapplication to a subject comprises an elongated support element having alength of between about 1.8 cm and about 4 cm, such as a length ofbetween about 1.8 cm and about 3 cm. The support element comprises oneor more electrodes fixed thereto in a vicinity of a distal end thereof.The stimulation system further comprises a control unit, coupled to thesupport element in a vicinity of a proximal end thereof. The controlunit typically comprises a battery, and is adapted to drive theelectrodes to apply an electrical current to tissue of the subject, suchas the SPG system and/or at least one MTS. The control unit typicallyconfigures the current to have a pulse frequency of between about 10 Hzand about 50 Hz, an amplitude of between about 0.2 V and about 10 V, apulse width of between about 50 microseconds and about 5 milliseconds,and, in alternation, on periods of between about 1 second and about 2minutes, and off periods of between about 1 second and about 2 minutes.(Together, the on and off periods define a duty cycle.) For example, thecontrol unit may drive the electrodes to apply the current having onperiods of between about 60 seconds and about 105 seconds, and offperiods of between about 30 seconds and 90 seconds, e.g., on periods ofabout 90 seconds, and off periods of about 60 seconds.

For some applications, the support element is semi-rigid. For example,the support element and the electrodes together may be similar toconventional concentric needle electrodes, such as Medtronic, Inc.needle electrode model DCN50, or Oxford Instruments Plc. needleelectrode models X53153, X53155, X53156, X53158, or X53159.

For some applications, the stimulation system comprises an oralappliance, coupled to the support element, and shaped so as to define asurface that fits closely to a roof of an oral cavity. For example, theoral appliance may be similar to oral appliance 518, describedhereinabove with reference to FIG. 18. For some applications, thecontrol unit has a volume, including the battery, of less than about 3cm³.

In an embodiment of the present invention, a stimulation system forapplication to a subject comprises an elongated support element having alength of between about 1.8 cm and about 4 cm, such as a length ofbetween about 1.8 cm and about 3 cm. The support element comprises oneor more electrodes fixed thereto in a vicinity of a distal end thereof,and a receiver, fixed to the support element in a vicinity of theproximal end thereof. The stimulation system further comprises a controlunit, adapted to be coupled to the receiver. The control unit is adaptedto drive the electrodes via the receiver to apply an electrical currentto tissue of the subject, such as the SPG system and/or at least oneMTS. The control unit typically configures the current to have a pulsefrequency of between about 10 Hz and about 50 Hz, an amplitude ofbetween about 0.2 V and about 10 V, a pulse width of between about 50microseconds and about 5 milliseconds, and, in alternation, on periodsof between about 1 second and about 2 minutes, and off periods ofbetween about 1 second and about 2 minutes. (Together, the on and offperiods define a duty cycle.) For example, the control unit may drivethe electrodes to apply the current having on periods of between about60 seconds and about 105 seconds, and off periods of between about 30seconds and 90 seconds, e.g., on periods of about 90 seconds, and offperiods of about 60 seconds.

For some applications, the receiver comprises an electrical contactsite, and the control unit is adapted to be coupled to the receiver bybeing brought into physical contact with the electrical contact site.For example, the control unit may be brought into physical contact bypositioning the control unit inside an oral cavity of the subject. Forsome applications, the stimulation system comprises an oral appliance,adapted to be fixed to the control unit, and shaped so as to define asurface that fits closely to a roof of an oral cavity. For example, theoral appliance may be similar to oral appliance 518, describedhereinabove with reference to FIG. 18.

Alternatively, the receiver comprises a transducer, and the control unitcomprises a wireless transmitter, which is adapted to couple the controlunit to the receiver via wireless electromagnetic communication with thetransducer. Typically, the transducer comprises a coil. For someapplications, the control unit is adapted to be positioned outside of ahead of the subject. Alternatively, the control unit is adapted to beplaced in the oral cavity, such as by being fixed to an oral appliance.For some applications, the receiver has a volume of less than about 0.8cm³, such as less than about 0.15 cm³.

For some applications, stimulator 30 is implanted using techniquesdescribed in a US patent application filed May 11, 2005, entitled,“Surgical tools and techniques for stimulation,” which is assigned tothe assignee of the present application and is incorporated herein byreference.

In the present patent application, “SPG system” means the SPG andassociated neuroanatomical structures, including neural tractsoriginating in or reaching the SPG, including outgoing and incomingparasympathetic and sympathetic tracts, which tracts includepreganglionic fibers of the SPG (e.g., fibers contained within thevidian nerve) and postganglionic fibers of the SPG (fibers that travelanterogradely from the SPG toward the brain vascular bed, including theretro-orbital branches of the SPG, which are fibers that connect the SPGwith orbital neural structures).

In an embodiment of the present invention, during placement ofelectrodes 38 at an MTS, as defined hereinabove, at least onephysiological indicator of cerebral blood flow (CBF) is observed ormeasured concurrently with or after placement. For some applications,optimization of placement of electrodes 38 onto the appropriate neuralstructure is performed by activating the stimulator, and generallysimultaneously monitoring CBF while manipulating the electrodes, and/oradjusting at least one parameter of the applied stimulation, so as toincrease or decrease CBF, as appropriate. Alternatively or additionally,this technique is used to verify the placement of electrodes 38 afterimplantation, and/or to select which combination of electrodes to use,such as by using the feedback algorithm described hereinabove.Alternatively or additionally, a similar optimization process isperformed, either during or after placement of electrodes 38, todetermine parameters of the applied current so as to achieve a desiredeffect, e.g., on CBF or BBB permeability, as indicated by CBF.

Physiological indicators of CBF include, but are not limited to, thefollowing:

-   -   a measure of vasodilation of blood vessels of the eye,        determined by unaided visual inspection or by using an        instrument, e.g., an instrument comprising machine vision        functionality;    -   transcranial Doppler ultrasonography measurements;    -   a measure of forehead perfusion, measured, for example, using        laser Doppler perfusion imaging (LDI) and/or using a temperature        sensor; and/or    -   near infrared spectroscopy (NIRS) measurements.

Other appropriate measurements indicative of CBF for use with theseembodiments of the present invention will be apparent to those skilledin the art, having read the disclosure of the present patentapplication.

For some applications, one or more of the devices described hereinbelowwith reference to FIGS. 18-21 are used for assessing a physiologicalindicator of CBF.

FIG. 19 is a schematic illustration of a vasodilation measurementinstrument 230, in accordance with an embodiment of the presentinvention. Instrument 230 comprises an image sensor 234 (e.g., a CCD orCMOS sensor, or another camera) and processing circuitry 238, in orderto provide machine vision functionality. Image sensor 234 is directedtowards an eye 232 of the subject. The instrument measures the ratio ofred to white in the sclera of eye 232, or another indication ofvasodilation.

FIG. 20 is a schematic illustration of a laser Doppler perfusion (LDI)device 270, in accordance with an embodiment of the present invention.LDI device 270 comprises a laser source 271, a scanner 272, and acomputer 281. Scanner 272 is positioned near a forehead 241 of thesubject for measuring forehead perfusion.

FIG. 21 is a schematic illustration of a thermometer 280, in accordancewith an embodiment of the present invention. Thermometer 280 ispositioned touching a forehead 241 of the subject for measuring foreheadperfusion.

FIG. 22 is a schematic illustration of a transcranial Dopplerultrasonography device 284, in accordance with an embodiment of thepresent invention. Transcranial Doppler ultrasonography device 284 ispositioned touching a head 288 of the subject for measuring CBF.

For some applications, the measurement device, such as those describedhereinabove with reference to FIGS. 18-21, comprises an output unit 236,such as a numeric display, tone generator, color display, or otheroutput device, for outputting a signal indicative of the measuredphysiological parameter. Alternatively or additionally, instrument 230is coupled to an internal or external control unit of system 20 or 120,and communicates the signal directly to the control unit.

In an embodiment of the present invention, during placement ofelectrodes 38 at an MTS, as defined hereinabove, penetration of asystemically administered dye into an eye of the subject is observed ormeasured concurrently with or after placement, as an indication of alevel of increased permeability of the BBB. For example, the dye mayinclude fluorescein dye. For some applications, optimization ofplacement of electrodes 38 onto the appropriate neural structure isperformed by activating the stimulator, and generally simultaneouslymonitoring the penetration of the dye while manipulating the electrodes,and/or adjusting at least one parameter of the applied stimulation, soas to increase or decrease permeability of the BBB, as appropriate.Alternatively or additionally, this technique is used to verify theplacement of electrodes 38 after implantation, and/or to select whichcombination of electrodes to use, such as by using the feedbackalgorithm described hereinabove. Alternatively or additionally, asimilar optimization process is performed, either during or afterplacement of electrodes 38, to determine parameters of the appliedcurrent so as to achieve a desired effect, e.g., on CBF or BBBpermeability, as indicated by BBB permeability.

In an embodiment of the present invention, one or more of theabove-described CBF-based assessment techniques are used by a healthcareworker after implantation to assess (a) whether electrodes 38 retainappropriate placement and contact with the MTS, and/or (b) whetherparameters of the applied current (e.g., magnitude, frequency, duration,scheduling) continue to achieve the desired effect, e.g., on CBF or BBBpermeability. For example, such an assessment may be performedperiodically during post-implantation follow-up care.

In an embodiment of the present invention, the CBF-based assessmenttechniques described hereinabove are used to assist in determining theeffective dosage and/or other parameters for presenting odorants to anair passage of the patient, as described in U.S. patent application Ser.No. 10/512,780, filed Oct. 25, 2004, which is assigned to the assigneeof the present application and is incorporated herein by reference.

In an embodiment of the present invention, chemical stimulation of atleast one MTS is achieved by presenting chemicals, for example in aliquid or gaseous state, to an air passage of the subject, such as anasal cavity or a throat, or in a vicinity thereof. The temporal profileand other quantitative characteristics of such chemical modulation arebelieved by the present inventors to have a mechanism of action that hasa neuroanatomical basis overlapping with that of the electricalmodulation of the MTS. For some applications, chemical-presentationtechniques described herein are practiced in combination with techniquesdescribed in U.S. patent application Ser. No. 10/512,780, filed Oct. 25,2004, and/or U.S. patent application Ser. No. 10/952,536, filed Sep. 27,2005, both of which are assigned to the assignee of the present patentapplication and are incorporated herein by reference. In thesechemical-presentation applications, an extent to which the chemical hasachieved the desired effect (e.g., increased permeability of the BBB, orincreased or decreased CBF) is determined by monitoring real-timechanges in CBF, and adjusting the dose of the chemical responsivethereto.

Chemicals that may increase or decrease cerebral blood flow and/or thepermeability of the blood-brain barrier (e.g., via modulation ofSPG-related fibers), include, but are not limited to, propionic acid,cyclohexanone, amyl acetate, acetic acid, citric acid, carbon dioxide,sodium chloride, ammonia, menthol, alcohol, nicotine, piperine,gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde,cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, andeucalyptol. The chemicals reach the appropriate neural structures andinduce vasodilatation, vasoconstriction and/or cerebrovascularpermeability changes.

In an embodiments of the present invention, chemical stimulation isapplied to at least one MTS, using (a) a nasal applicator adapted todeliver the stimulating chemical to an upper region of the nasal cavity,or (b) a transpalatine applicator inserted via the greater palatinecanal.

In some embodiments of the present invention, stimulation of at leastone MTS is achieved by applying a neuroexcitatory agent to the MTS.Suitable neuroexcitatory agents include, but are not limited to,acetylcholine and urocholine. For some applications, the MTS isstimulated by applying a neuroinhibitory agent, such as atropine,hexamethonium, or a local anesthetic (e.g., lidocaine). In theseagent-application embodiments, an extent to which the agent has achievedthe desired effect (e.g., increased permeability of the BBB, orincreased or decreased CBF) is determined by monitoring real-timechanges in CBF, and adjusting the dose of the agent responsive thereto.

In an embodiment of the present invention, stimulation of the MTS isachieved by applying mechanical stimulation to the MTS, e.g., vibration.An extent to which the mechanical stimulation has achieved the desiredeffect (e.g., increased permeability of the BBB, or increased ordecreased CBF) is determined by monitoring real-time changes in CBF, andadjusting the extent of the mechanical stimulation (e.g., magnitude,frequency, or duration) responsive thereto.

It is also to be appreciated that whereas some embodiments of thepresent invention are described with respect to implanting theelectrical stimulator, for some applications the stimulator istemporarily inserted into the subject, and techniques described hereinare used to optimize the temporary placement of the stimulator.

In an embodiment of the present invention, bilateral stimulation isapplied, in which a first electrode is applied to a first MTS, and asecond electrode is applied to a second MTS. Such bilateral stimulationmay be applied using techniques described in U.S. Provisional PatentApplication 60/604,037, filed Aug. 23, 2004, which is assigned to theassignee of the present application and is incorporated herein byreference, and/or in PCT Patent Application PCT/IL2005/000912, filedAug. 23, 2005,” entitled, “Concurrent bilateral SPG modulation,” whichis assigned to the assignee of the present application and isincorporated herein by reference.

In some embodiments of the present invention, techniques describedherein are practiced in combination with techniques described in one ormore of the references cited in the Background of the Invention sectionhereinabove and/or in combination with techniques described in one ormore of the patent applications cited hereinabove.

The scope of the present invention includes embodiments described in thefollowing patent applications, which are assigned to the assignee of thepresent patent application and are incorporated herein by reference. Inan embodiment of the present invention, techniques and apparatusdescribed in one or more of the following applications are combined withtechniques and apparatus described herein:

-   -   U.S. Provisional Patent Application 60/203,172, filed May 8,        2000, entitled, “Method and apparatus for stimulating the        sphenopalatine ganglion to modify properties of the BBB and        cerebral blood flow”    -   U.S. patent application Ser. No. 10/258,714, filed Oct. 25,        2002, entitled, “Method and apparatus for stimulating the        sphenopalatine ganglion to modify properties of the BBB and        cerebral blood flow,” or the above-referenced PCT Publication WO        01/85094    -   U.S. Provisional Patent Application 60/364,451, filed Mar. 15,        2002, entitled, “Applications of stimulating the sphenopalatine        ganglion (SPG)”    -   U.S. Provisional Patent Application 60/368,657, filed Mar. 28,        2002, entitled, “SPG Stimulation”    -   U.S. Provisional Patent Application 60/376,048, filed Apr. 25,        2002, entitled, “Methods and apparatus for modifying properties        of the BBB and cerebral circulation by using the neuroexcitatory        and/or neuroinhibitory effects of odorants on nerves in the        head”    -   U.S. Provisional Patent Application 60/388,931, filed Jun. 14,        2002, entitled “Methods and systems for management of        Alzheimer's disease,” PCT Patent Application PCT/IL03/000508,        filed Jun. 13, 2003, claiming priority therefrom, and U.S.        patent application Ser. No. 10/518,322, filed Dec. 14, 2004 in        the national stage thereof    -   U.S. Provisional Patent Application 60/400,167, filed Jul. 31,        2002, entitled, “Delivering compounds to the brain by modifying        properties of the BBB and cerebral circulation”    -   U.S. Provisional Patent Application 60/426,180, filed Nov. 14,        2002, entitled, “Surgical tools and techniques for        sphenopalatine ganglion stimulation,” PCT Patent Application        PCT/IL03/000966, filed Nov. 13, 2003, which claims priority        therefrom, and U.S. patent application Ser. No. 10/535,024,        filed May 11, 2005, in the national stage thereof    -   U.S. Provisional Patent Application 60/426,182, filed Nov. 14,        2002, and corresponding PCT Patent Application PCT/IL03/000967,        which claims priority therefrom, filed Nov. 13, 2003, entitled,        “Stimulation circuitry and control of electronic medical        device,” and a US patent application filed May 11, 2005 in the        national stage thereof    -   U.S. patent application Ser. No. 10/294,310, filed Nov. 14,        2002, entitled, “SPG stimulation for treating eye pathologies,”        and PCT Patent Application PCT/IL03/000965, filed Nov. 13, 2003,        claiming priority therefrom    -   PCT Patent Application PCT/IL03/000631, filed Jul. 31, 2003,        entitled, “Delivering compounds to the brain by modifying        properties of the BBB and cerebral circulation,” and a US patent        application filed Jan. 31, 2005 in the national stage thereof    -   U.S. Pat. No. 6,853,858 to Shalev    -   U.S. patent application Ser. No. 10/783,113, filed Feb. 20,        2004, entitled, “Stimulation for acute conditions”    -   U.S. Provisional Patent Application 60/426,181, filed Nov. 14,        2002, entitled, “Stimulation for treating ear pathologies,” PCT        Patent Application PCT/IL03/000963, filed Nov. 13, 2003, which        claims priority therefrom, and a US patent application filed May        11, 2005 in the national stage thereof    -   U.S. Provisional Patent Application 60/448,807, filed Feb. 20,        2003, entitled, “Stimulation for treating autoimmune-related        disorders of the CNS”    -   U.S. Provisional Patent Application 60/461,232 to Gross et al.,        filed Apr. 8, 2003, entitled, “Treating abnormal conditions of        the mind and body by modifying properties of the blood-brain        barrier and cephalic blood flow”    -   PCT Patent Application PCT/IL03/00338 to Shalev, filed Apr. 25,        2003, entitled, “Methods and apparatus for modifying properties        of the BBB and cerebral circulation by using the neuroexcitatory        and/or neuroinhibitory effects of odorants on nerves in the        head,” and U.S. patent application Ser. No. 10/512,780, filed        Oct. 25, 2004 in the national stage thereof    -   U.S. Provisional Patent Application 60/506,165, filed Sep. 26,        2003, entitled, “Diagnostic applications of stimulation”    -   U.S. patent application Ser. No. 10/678,730, filed Oct. 2, 2003,        entitled, “Targeted release of nitric oxide in the brain        circulation for opening the BBB,” and PCT Patent Application        PCT/IL04/000911, filed Oct. 3, 2004, claiming priority therefrom    -   PCT Patent Application PCT/IL04/000897, filed Sep. 26, 2004,        entitled, “Stimulation for treating and diagnosing conditions”    -   U.S. Provisional Patent Application 60/604,037, filed Aug. 23,        2004, entitled, “Concurrent bilateral SPG modulation”    -   PCT Patent Application PCT/IL2005/000912, filed Aug. 23, 2005,        entitled, “Concurrent bilateral SPG modulation”    -   U.S. patent application Ser. No. 10/952,536, filed Sep. 27,        2004, entitled, “Stimulation for treating and diagnosing        conditions”    -   U.S. Provisional Patent Application 60/709,734, filed Aug. 19,        2005, entitled, “Stimulation for treating brain events and other        conditions”

In an embodiment of the present invention, system 20 and/or 120comprises circuitry described in one or more of the above-mentionedapplications.

As used in the present application, the BBB comprises the tightjunctions opposing the passage of most ions and large molecular weightcompounds between the blood and brain tissue.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description. For example, elementswhich are shown in a figure to be housed within one integral unit may,for some applications, be disposed in a plurality of distinct units.Similarly, apparatus for communication and power transmission which areshown to be coupled in a wireless fashion may, alternatively, be coupledin a wired fashion, and apparatus for communication and powertransmission which are shown to be coupled in a wired fashion may,alternatively, be coupled in a wireless fashion.

1.-236. (canceled)
 237. Apparatus for modifying a property of a brain ofa subject, comprising: at least one electrode, configured to bepositioned in a vicinity of a mucous membrane of a palate of an oralcavity of the subject; and a control unit, configured to drive theelectrode to apply an electrical current to the mucous membrane, and toconfigure the current to be capable of inducing an increase in cerebralblood flow (CBF) of the subject.
 238. The apparatus according to claim237, and comprising an oral appliance, which comprises the at least oneelectrode.
 239. The apparatus according to claim 237, wherein thecontrol unit is configured to configure the current to have a magnitudesufficient to activate a sphenopalatine ganglion (SPG) of the subjectvia nerve fibers in physical contact with the mucous membrane.
 240. Theapparatus according to claim 237, wherein the control unit is configuredto configure the current to increase the CBF to a magnitude sufficientto treat a condition of the subject.
 241. A method for modifying aproperty of a brain of a subject, comprising: applying an electricalcurrent to a mucous membrane of a palate of an oral cavity of thesubject; and configuring the current to induce an increase in cerebralblood flow (CBF) of the subject.
 242. The method according to claim 241,comprising administering a sedative to the subject in conjunction withapplying the current.
 243. The method according to claim 241, comprisingadministering an anesthetic to the subject in conjunction with applyingthe current.
 244. The method according to claim 241, wherein applyingthe current comprises configuring the current to have a magnitudesufficient to activate a sphenopalatine ganglion (SPG) of the subjectvia nerve fibers in physical contact with the mucous membrane.
 245. Themethod according to claim 241, wherein applying the current comprisesconfiguring the current to increase the CBF to a magnitude sufficient totreat a condition of the subject.
 246. The method according to claim241, wherein applying the current comprises bringing an oral applianceinto contact with the mucous membrane, and applying the current from theoral appliance.